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Baldwin, Paige; Sridhar, Srinivas; Singh, Bijay Nanoencapsulated combination drug formulations Miscellaneous 2023, (US Patent 11,648,211). Sridhar, Srinivas True superconductivity at near ambient temperature has not been confirmed by Dasenbrock-Gammon, et. al. Nature (2023) Journal Article In: arXiv preprint arXiv:2303.05987, 2023. Yang, Shicheng; Green, Allen; Brown, Needa; Robinson, Alexis; Senat, Merline; Testino, Bryanna; Dinulescu, Daniela M; Sridhar, Srinivas Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer Journal Article In: Frontiers in Oncology, vol. 13, pp. 1175617, 2023. Sridhar, Srinivas True superconductivity at near ambient temperature has not been confirmed by Dasenbrock-Gammon et al. Nature, volume 615, pages 244–250 (2023) Journal Article In: Journal of Physics and Chemistry of Solids, pp. 111381, 2023. Kunjachan, Sijumon; Detappe, Alexandre; Kumar, Rajiv; Ireland, Thomas; Cameron, Lisa; Biancur, Douglas E; Motto-Ros, Vincent; Sancey, Lucie; Sridhar, Srinivas; Makrigiorgos, G Mike; others, Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy (Retraction of Vol 15, Pg 7488, 2015) Miscellaneous 2022. Thong, Phan Quoc; Huong, Le Thi Thu; Tu, Nguyen Dac; Nhung, Hoang Thi My; Khanh, Lam; Manh, Do Hung; Nam, Pham Hong; Phuc, Nguyen Xuan; Alonso, Javier; Qiao, Ju; others, Multifunctional nanocarriers of Fe3O4@ PLA-PEG/curcumin for MRI, magnetic hyperthermia and drug delivery Journal Article In: Nanomedicine, no. 0, 2022. Rodell, Christopher B; Baldwin, Paige; Fernandez, Bianca; Weissleder, Ralph; Sridhar, Srinivas; Dubach, John Matthew Quantification of cellular drug biodistribution addresses challenges in evaluating in vitro and in vivo encapsulated drug delivery Journal Article In: Advanced therapeutics, vol. 4, no. 3, pp. 2000125, 2021. Zhang, Di; Singh, Bijay; Moerland, Jessica; Mitchell, Owen; Lockwood, Lizbeth; Carapellucci, Sarah; Sridhar, Srinivas; Liby, Karen T Sustained, local delivery of the PARP inhibitor talazoparib prevents the development of mammary gland hyperplasia in BRCA1-deficient mice Journal Article In: Scientific Reports, vol. 11, no. 1, pp. 1234, 2021. Yang, Shicheng; Wallach, Mia; Krishna, Apurva; Kurmasheva, Raushan; Sridhar, Srinivas Recent developments in nanomedicine for pediatric cancer Journal Article In: Journal of Clinical Medicine, vol. 10, no. 7, pp. 1437, 2021. Timms, Liam; Zhou, Tianyi; Lyu, Yue; Qiao, Ju; Mishra, Vishala; Lahoud, Rita Maria; Jayaraman, Gayatri Veeramani; Allegretti, Andrew S; Drew, David; Seethamraju, Ravi T; others, Ferumoxytol-enhanced ultrashort TE MRA and quantitative morphometry of the human kidney vasculature Journal Article In: Abdominal Radiology, vol. 46, pp. 3288–3300, 2021. Versek, Craig; Banijamali, S Mohammad Ali; Bex, Peter; Lashkari, Kameran; Kamarthi, Sagar; Sridhar, Srinivas Portable diagnostic system for age-related macular degeneration screening using visual evoked potentials Journal Article In: Eye and brain, pp. 111–127, 2021. Cohen, Susan E; Hashmi, Sara M; III, A-Andrew D Jones; Lykourinou, Vasiliki; Ondrechen, Mary Jo; Sridhar, Srinivas; Ven, Anne L; Waters, Lauren S; Beuning, Penny J Adapting undergraduate research to remote work to increase engagement Journal Article In: The Biophysicist, vol. 2, no. 2, pp. 28–32, 2021. Wilfred, NGWA; Kumar, Rajiv; Makrigiorgos, Gerassimos; Sridhar, Srinivas; Dougan, Stephanie Biomaterials for combined radiotherapy and immunotherapy of cancer Miscellaneous 2020, (US Patent 10,835,604). Versek, Craig William; Banijamali, Mohammad Ali S; Bex, Peter J; Lashkari, Kameran; Kamarthi, Sagar V; Sridhar, Srinivas Portable Objective Diagnostics using Visual Evoked Potentials for Age-related Macular Degeneration Journal Article In: medRxiv, 2020. Cheng, Ming J; Mitra, Ronodeep; Okorafor, Chinedu C; Nersesyan, Alina A; Harding, Ian C; Bal, Nandita N; Kumar, Rajiv; Jo, Hanjoong; Sridhar, Srinivas; Ebong, Eno E Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity Journal Article In: Annals of Biomedical Engineering, pp. 1–14, 2020. Versek, Craig; Banijamali, S Mohammad Ali; Bex, Peter J; Lashkari, Kameran; Kamarthi, Sagar V; Sridhar, Srinivas Portable Objective Diagnostics using Visual Evoked Potentials for Age-related Macular Degeneration Journal Article In: medRxiv, pp. 2020–01, 2020. Cheng, Ming J; Mitra, Ronodeep; Okorafor, Chinedu C; Nersesyan, Alina A; Harding, Ian C; Bal, Nandita N; Kumar, Rajiv; Jo, Hanjoong; Sridhar, Srinivas; Ebong, Eno E Targeted intravenous nanoparticle delivery: role of flow and endothelial glycocalyx integrity Journal Article In: Annals of biomedical engineering, vol. 48, pp. 1941–1954, 2020. Mitra, Ronodeep; Qiao, Ju; Madhavan, Sudharsan; O’Neil, Gerard; Ritchie, Bailey; Kulkarni, Praveen; Sridhar, Srinivas; Ven, Anne; Cherry, Erica; Ferris, Craig; others, High fat diet versus disturbed blood flow conditions: Implications for endothelial glycocalyx integrity and pre-atherosclerotic inflammation Journal Article In: The FASEB Journal, vol. 34, no. S1, pp. 1–1, 2020. Schuemann, Jan; Bagley, Alexander F; Berbeco, Ross; Bromma, Kyle; Butterworth, Karl T; Byrne, Hilary L; Chithrani, B Devika; Cho, Sang Hyun; Cook, Jason R; Favaudon, Vincent; others, Roadmap for metal nanoparticles in radiation therapy: Current status, translational challenges, and future directions Journal Article In: Physics in Medicine & Biology, vol. 65, no. 21, pp. 21RM02, 2020. Virani, Needa A; Kelada, Olivia J; Kunjachan, Sijumon; Detappe, Alexandre; Kwon, Jihun; Hayashi, Jennifer; Vazquez-Pagan, Ana; Biancur, Douglas E; Ireland, Thomas; Kumar, Rajiv; others, Noninvasive imaging of tumor hypoxia after nanoparticle-mediated tumor vascular disruption Journal Article In: Plos one, vol. 15, no. 7, pp. e0236245, 2020. Mueller, Romy; Yasmin-Karim, Sayeda; DeCosmo, Kaylie; Vazquez-Pagan, Ana; Sridhar, Srinivas; Kozono, David; Hesser, Juergen; Ngwa, Wilfred Increased carcinoembryonic antigen expression on the surface of lung cancer cells using gold nanoparticles during radiotherapy Journal Article In: Physica Medica, vol. 76, pp. 236–242, 2020. Zhang, Di; Singh, Bijay; Moerland, Jessica; Mitchell, Owen; Lockwood, Lizbeth; Carapellucci, Sarah; Sridhar, Srinivas; Liby, Karen Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer Journal Article In: Cancer Research, vol. 80, no. 16_Supplement, pp. 12–12, 2020. Kunjachan, Sijumon; Kotb, Shady; Pola, Robert; Pechar, Michal; Kumar, Rajiv; Singh, Bijay; Gremse, Felix; Taleeli, Reza; Trichard, Florian; Motto-Ros, Vincent; others, Author correction: Selective priming of tumor Blood Vessels by Radiation therapy enhances nanodrug Delivery Journal Article In: Scientific Reports, vol. 10, no. 1, pp. 15344, 2020. Singh, Bijay; Yang, Shicheng; Krishna, Apurva; Sridhar, Srinivas Nanoparticle formulations of poly (ADP-ribose) polymerase inhibitors for cancer therapy Journal Article In: Frontiers in Chemistry, vol. 8, pp. 594619, 2020. TANGUTOORI, Shifalika; Sridhar, Srinivas Nanoparticle drug delivery system and method of treating cancer and neurotrauma Miscellaneous 2020. Mitra, Ronodeep; Cheng, Ming; O'Neil, Gerard; Kulkarni, Praveen; Kumar, Rajiv; Sridhar, Srinivas; Ferris, Craig; Hamilton, James; Jo, Hanjoong; Ebong, Eno E In Vivo Flow-Regulated Endothelial Glycocalyx Integrity Leveraged for Targeted Intravenous Nanoparticle Delivery Proceedings Article In: 2020 Virtual AIChE Annual Meeting, AIChE 2020. Sridhar, Srinivas; Versek, Craig; Bex, Peter Portable brain and vision diagnostic and therapeutic system Miscellaneous 2019, (US Patent App. 16/347,049). Cheng, Ming J; Bal, Nandita N; Prabakaran, Priya; Kumar, Rajiv; Webster, Thomas J; Sridhar, Srinivas; Ebong, Eno E Ultrasmall gold nanorods: synthesis and glycocalyx-related permeability in human endothelial cells Journal Article In: International journal of nanomedicine, vol. 14, pp. 319, 2019. Baldwin, Paige; Ohman, Anders W; Medina, Jamie Edward; McCarthy, Eric Timothy; Dinulescu, Daniela M; Sridhar, Srinivas Nanoformulation of talazoparib delays tumor progression and ascites formation in a late stage cancer model Journal Article In: Frontiers in oncology, vol. 9, pp. 353, 2019. Versek, Craig; Rissmiller, Armen; Tran, Anthony; Taya, Munish; Chowdhury, Kaushik; Bex, Peter; Sridhar, Srinivas Portable system for neuro-optical diagnostics using virtual reality display Journal Article In: Military medicine, vol. 184, no. Supplement_1, pp. 584–592, 2019. Kelada, Olivia J; Kunjachan, Sijumon; Virani, Needa A; Detappe, Alexandre; Hayashi, Jennifer; Ireland, Thomas; Biancur, Douglas E; Kumar, Rajiv; Sridhar, Srinivas; Makrigiorgos, Mike; others, Noninvasive imaging of tumor hypoxia during radiation-induced tumor vascular disruption Miscellaneous 2019. Baldwin, Paige; Orriols, Adrienne; Sridhar, Srinivas Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib Miscellaneous 2019. Singh, Bijay; Abdelhalim, Mostafa; Warrington, Stephanee; Sridhar, Srinivas Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer Miscellaneous 2019. Sridhar, Srinivas; Versek, Craig; Banijamali, Ali; Tran, Anthony; Cardozo, Armando; Lashkari, Kameran; Bex, Peter Portable VEP Diagnostics for NeuroVisual Disorders Journal Article In: Investigative Ophthalmology & Visual Science, vol. 60, no. 9, pp. 3591–3591, 2019. Zhang, Paige Baldwin Di; Leal, Ana S; Carapellucci, Sarah; Sridhar, Srinivas; Liby, Karen T A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice Journal Article In: Theranostics, vol. 9, no. 21, pp. 6224, 2019. Qiao, Ju; Cai, Xuezhu; Xiao, Qian; Chen, Zhengxi; Kulkarni, Praveen; Ferris, Craig; Kamarthi, Sagar; Sridhar, Srinivas Data on MRI brain lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization Journal Article In: Data in brief, vol. 27, pp. 104628, 2019. Bal, Nandita; Cheng, Ming; Kumar, Rajiv; Sridhar, Srinivas; Ebong, Eno E In Vivo Endothelial Uptake of Nanoparticles: Impact of Disturbed Flow and Degraded Glycocalyx Proceedings Article In: 2019 AIChE Annual Meeting, AIChE 2019. Kunjachan, Sijumon; Kotb, Shady; Pola, Robert; Pechar, Michal; Kumar, Rajiv; Singh, Bijay; Gremse, Felix; Taleeli, Reza; Trichard, Florian; Motto-Ros, Vincent; others, Selective priming of tumor Blood Vessels by Radiation therapy enhances nanodrug Delivery Journal Article In: Scientific reports, vol. 9, no. 1, pp. 1–14, 2019. Baldwin, Paige; Ohman, Anders; Medina, Jamie; Dinulescu, Daniela; Sridhar, Srinivas Abstract NT-087: NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL Miscellaneous 2019. Baldwin, Paige; Likhotvorik, Rostislav; Baig, Nabeela; Cropper, Jodie; Carlson, Ruth; Kurmasheva, Raushan; Sridhar, Srinivas Nanoformulation of talazoparib increases maximum tolerated doses in combination with temozolomide for treatment of Ewing sarcoma Journal Article In: Frontiers in Oncology, vol. 9, pp. 1416, 2019. Singh, Bijay; Yang, Shicheng; Baldwin, Paige; van de Ven, Anne; Sridhar, Srinivas Abstract A104: Nanoformulations of PARP and CDK inhibitors for cancer therapy Miscellaneous 2019. Baldwin, Paige; Ohman, Anders; Medina, Jamie; Dinulescu, Daniela; Sridhar, Srinivas NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL Proceedings Article In: CLINICAL CANCER RESEARCH, pp. 198–198, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2019. Cheng, Ming J; Prabakaran, Priya; Kumar, Rajiv; Sridhar, Srinivas; Ebong, Eno E Synthesis of functionalized 10-nm polymer-coated gold particles for endothelium targeting and drug delivery Journal Article In: JoVE (Journal of Visualized Experiments), no. 131, pp. e56760, 2018. Gharagouzloo, Codi A; Timms, Liam; Qiao, Ju; Fang, Zihang; Nneji, Joseph; Pandya, Aniket; Kulkarni, Praveen; van de Ven, Anne L; Ferris, Craig; Sridhar, Srinivas Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge Journal Article In: Data in brief, vol. 17, pp. 393–396, 2018. Kunjachan, Sijumon; Kotb, Shady; Kumar, Rajiv; Pola, Robert; Pechar, Michal; Gremse, Felix; Taleeli, Reza; Trichard, Florian; Motto-Ros, Vincent; Sancey, Lucie; others, Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation Journal Article In: bioRxiv, pp. 268714, 2018. Gupta, Parul; Singh, Manjri; Kumar, Rajiv; Belz, Jodi; Shanker, Rishi; Dwivedi, Premendra D; Sridhar, Srinivas; Singh, Surinder P Synthesis and in vitro studies of PLGA-DTX nanoconjugate as potential drug delivery vehicle for oral cancer Journal Article In: International journal of nanomedicine, vol. 13, no. T-NANO 2014 Abstracts, pp. 67, 2018. Baronia, Richa; Singh, Manjri; Gupta, Rajat B; Karuppiah, Stalin; Kumar, Rajiv; Belz, Jodi; Shanker, Rishi; Sridhar, Srinivas; Singh, Surinder P Synthesis and characterization of multifunctional gold nanoclusters for application in radiation therapy Journal Article In: International journal of nanomedicine, vol. 13, no. T-NANO 2014 Abstracts, pp. 113, 2018. Baldwin, Paige; Tangutoori, Shifalika; Sridhar, Srinivas In vitro analysis of pArp inhibitor nanoformulations Journal Article In: International journal of nanomedicine, vol. 13, no. T-NANO 2014 Abstracts, pp. 59, 2018. Upponi, Jaydev R; Jerajani, Kaushal; Nagesha, Dattatri K; Kulkarni, Praveen; Sridhar, Srinivas; Ferris, Craig; Torchilin, Vladimir P Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents Journal Article In: Biomaterials, vol. 170, pp. 26–36, 2018. Versek, C; Frasca, T; Zhou, J; Chowdhury, K; Sridhar, S Electric field encephalography for brain activity monitoring Journal Article In: Journal of neural engineering, vol. 15, no. 4, pp. 046027, 2018. Thanh, Nguyen; Phuc, Xuan; Sridhar, Srinivas Nanoscale Magnetism in Next Generation Magnetic Nanoparticles Technical Report UNIVERSITY COLLEGE LONDON London United Kingdom 2018. Guthier, CV; D'Amico, AV; King, MT; Nguyen, PL; Orio, PF; Sridhar, S; Makrigiorgos, GM; Cormack, RA Determining optimal eluter design by modeling physical dose enhancement in brachytherapy Journal Article In: Medical physics, vol. 45, no. 8, pp. 3916–3925, 2018. Zhang, Di; Baldwin, Paige; Sridhar, Srinivas; Liby, Karen Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer Miscellaneous 2018. Vazquez-Pagan, Ana G; Baldwin, Paige; Ashtaputre, Ravina M; Kunjachan, Sijumon; Sridhar, Srinivas; Kumar, Rajiv; Berbeco, Ross Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer Miscellaneous 2018. Baldwin, Paige; Kumar, Rajiv; Sridhar, Srinivas Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment Miscellaneous 2018. Kunjachan, S; Kotb, S; Kumar, R; Pola, R; Pechar, M; Gremse, F; Taleei, R; Trichard, F; Motto-Ros, V; Sancey, L; others, BEST IN PHYSICS (THERAPY): Enhanced Drug Delivery by Nanoparticle and Radiation-Mediated Tumor Vascular Modulation Proceedings Article In: MEDICAL PHYSICS, pp. E535–E535, WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA 2018. Zhang, Di; Baldwin, Paige; Sridhar, Srinivas; Liby, Karen Nanoformulated Talazoparib enhances the efficacy and reduces the toxicity of this PARP inhibitor in a preclinical model of BRCA-deficient breast cancer Journal Article In: The FASEB Journal, vol. 32, no. 1_supplement, pp. 565–10, 2018. Mitra, Ronodeep; Qiao, Ju; Madhavan, Sudharsan; O’Neil, Gerard L; Ritchie, Bailey; Kulkarni, Praveen; Sridhar, Srinivas; van de Ven, Anne L; Kemmerling, Erica Cherry M; Ferris, Craig; others, The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation Journal Article In: Translational medicine communications, vol. 3, no. 1, pp. 1–15, 2018. Baldwin, Paige; Ohman, Anders W; Tangutoori, Shifalika; Dinulescu, Daniela M; Sridhar, Srinivas Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment Journal Article In: International journal of nanomedicine, vol. 13, pp. 8063, 2018. Faegh, Samira; Jalili, Nader; Sridhar, Srinivas Sensor system utilizing piezoelectric microcantilever coupled with resonating circuit Miscellaneous 2018, (US Patent 9,921,226). Wilfred, NGWA; Kumar, Rajiv; Makrigiorgos, Gerassimos; Sridhar, Srinivas; Dougan, Stephanie Biomaterials for combined radiotherapy and immunotherapy of cancer Miscellaneous 2018, (US Patent App. 15/752,099). Barlow, Jacob; Gozzi, Kevin; Kelley, Chase P; Geilich, Benjamin M; Webster, Thomas J; Chai, Yunrong; Sridhar, Srinivas; van de Ven, Anne L High throughput microencapsulation of Bacillus subtilis in semi-permeable biodegradable polymersomes for selenium remediation Journal Article In: Applied microbiology and biotechnology, vol. 101, no. 1, pp. 455–464, 2017. Geilich, Benjamin M; Gelfat, Ilia; Sridhar, Srinivas; van de Ven, Anne L; Webster, Thomas J Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication Journal Article In: Biomaterials, vol. 119, pp. 78–85, 2017. Paro, Autumn D; Shanmugam, Ilan; van de Ven, Anne; Kumar, Rajiv; Webster, Thomas J; Sridhar, Srinivas Abstract B44: Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer Miscellaneous 2017. Baldwin, Paige; Ohman, Anders; Belz, Jodi; Thong, Jeremy; Ojo, Noelle Castilla; Liby, Karen; Dinulescu, Daniela; Sridhar, Srinivas Abstract B29: Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib Miscellaneous 2017. Codi, Gharagouzloo; Qiao, Ju; Timms, Liam; van de Ven, Anne; Sridhar, Srinivas Abstract B22: Quantitative tumor imaging using magnetic nanoparticles Miscellaneous 2017. van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Seitzer, Nina; Clohessy, John; Korideck, Houari; Makrigiorgos, Mike G; Cormack, Robert; others, Abstract B48: Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance Miscellaneous 2017. Kumar, Rajiv; Ngwa, Wilfred; Joshi, Vinit; Kunjachan, Sijumon; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas Abstract B41: Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy Miscellaneous 2017. Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Abstract B30: Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer Miscellaneous 2017. Belz, Jodi; Castilla-Ojo, Noelle; Sridhar, Srinivas; Kumar, Rajiv Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer Book Section In: Cancer Nanotechnology, pp. 403–409, Humana Press, New York, NY, 2017. Baldwin, Paige; Tangutoori, Shifalika; Sridhar, Srinivas Generation of Dose--Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations Book Section In: Cancer Nanotechnology, pp. 337–342, Humana Press, New York, NY, 2017. Guthier, Christian V; D'Amico, Anthony V; King, Martin T; Nguyen, Paul L; Orio, Peter F; Sridhar, Srinivas; Makrigiorgos, Mike G; Cormack, Robert A Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants Journal Article In: Brachytherapy, vol. 16, no. 3, pp. S115, 2017. van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Seitzer, Nina; Clohessy, John G; Makrigiorgos, Mike G; Cormack, Robert; Pandolfi, Pier Paolo; others, Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation Journal Article In: Molecular cancer therapeutics, vol. 16, no. 7, pp. 1279–1289, 2017. Baldwin, Paige; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER Miscellaneous 2017. Baldwin, Paige; Kumar, Rajiv; Favours, Edward; Liby, Karen; Kurmasheva, Raushan; Kozono, David; Sridhar, Srinivas Nanoformulated Talazoparib and Olaparib for enhanced delivery Miscellaneous 2017. Baig, Nabeela; Likhotvorik, Rostislav; Baldwin, Paige; Sridhar, Srinivas; Kurmasheva, Raushan Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts Miscellaneous 2017. Hachani, Roxanne; Birchall, Martin A; Lowdell, Mark W; Kasparis, Georgios; Tung, Le D; Manshian, Bella B; Soenen, Stefaan J; Gsell, Willy; Himmelreich, Uwe; Gharagouzloo, Codi A; others, Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging Journal Article In: Scientific reports, vol. 7, no. 1, pp. 1–14, 2017. Gharagouzloo, Codi A; Timms, Liam; Qiao, Ju; Fang, Zihang; Nneji, Joseph; Pandya, Aniket; Kulkarni, Praveen; van de Ven, Anne L; Ferris, Craig; Sridhar, Srinivas Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function Journal Article In: Neuroimage, vol. 163, pp. 24–33, 2017. Belz, Jodi E; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S; Royce, Darlene B; Zhang, Di; van de Ven, Anne L; Liby, Karen T; Sridhar, Srinivas Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer Journal Article In: Theranostics, vol. 7, no. 17, pp. 4340, 2017. Gharagouzloo, Codi; Sridhar, Srinivas Quantitative magnetic resonance imaging of the vasculature Miscellaneous 2017. Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer Proceedings Article In: CANCER RESEARCH, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2017. Kumar, Rajiv; Sridhar, Srinivas; Wilfred, NGWA; Cormack, Robert; Makrigiorgos, Gerassimos Biopolymer-Nanoparticle Composite Implant for Tumor Cell Tracking Miscellaneous 2017, (US Patent App. 15/328,711). Sridhar, Srinivas; Petrov, Yury; Yavuzcetin, Ozgur Electric field encephalography: electric field based brain signal detection and monitoring Miscellaneous 2016, (US Patent App. 14/420,613). Schuemann, Jan; Berbeco, Ross; Chithrani, Devika B; Cho, Sang Hyun; Kumar, Rajiv; McMahon, Stephen J; Sridhar, Srinivas; Krishnan, Sunil Roadmap to clinical use of gold nanoparticles for radiation sensitization Journal Article In: International Journal of Radiation Oncology* Biology* Physics, vol. 94, no. 1, pp. 189–205, 2016. Baldwin, Paige; Ohman, Anders; Thong, Jeremy; Tangutoori, Shifalika; Dinulescu, Daniela; Sridhar, Srinivas Abstract A03: PARP inhibitor nanotherapy for ovarian cancer. Miscellaneous 2016. Markovic, Stacey; Belz, Jodi; Kumar, Rajiv; Cormack, Robert A; Sridhar, Srinivas; Niedre, Mark Near-infrared fluorescence imaging platform for quantifying in vivo nanoparticle diffusion from drug loaded implants Journal Article In: International journal of nanomedicine, vol. 11, pp. 1213, 2016. Hau, Herman; Khanal, Dipesh; Rogers, Linda; Suchowerska, Natalka; Kumar, Rajiv; Sridhar, Srinivas; McKenzie, David; Chrzanowski, Wojciech Dose enhancement and cytotoxicity of gold nanoparticles in colon cancer cells when irradiated with kilo-and mega-voltage radiation Journal Article In: Bioengineering & translational medicine, vol. 1, no. 1, pp. 94–102, 2016. Sridhar, Srinivas; Petrov, Yury; Yavuzcetin, Ozgur; Chowdhury, Kaushik Sensor system and process for measuring electric activity of the brain, including electric field encephalography Miscellaneous 2016, (US Patent App. 14/896,511). Cormack, Robert A; Nguyen, Paul N; D'Amico, Anthony V; Sridhar, Srinivas; Makrigiorgos, Gerassimos Localized Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants Journal Article In: Brachytherapy, vol. 15, pp. S161–S162, 2016. Belz, J; Kumar, R; Makrigiorgos, G; D'Amico, A; Nguyen, P; Cormack, R; Sridhar, S WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer Journal Article In: Medical physics, vol. 43, no. 6Part41, pp. 3823–3823, 2016. Baldwin, Paige; Ohman, Anders; Thong, Jeremy; Tangutoori, Shifalika; van de Ven, Anne; Kumar, Rajiv; Dinulescu, Daniela; Sridhar, Srinivas Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy Miscellaneous 2016. Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer Miscellaneous 2016. Cheng, Ming J; Kumar, Rajiv; Sridhar, Srinivas; Webster, Thomas J; Ebong, Eno E Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting Journal Article In: International journal of nanomedicine, vol. 11, pp. 3305, 2016. Kunjachan, S; Detappe, A; Kumar, R; Sridhar, S; Makrigiorgos, GM; Berbeco, R PO-0983: Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy Journal Article In: Radiotherapy and Oncology, vol. 119, pp. S477–S478, 2016. Cormack, RA; Nguyen, PL; D'Amico, AV; Sridhar, S; Makrigiorgos, M In Situ Radiosensitization of Brachytherapy: Image Guided Planned Biologic Enhancement of Brachytherapy Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. E649, 2016. Baldwin, P; Ven, AL Van De; Seitzer, N; Clohessy, S; Cormack, RA; Makrigiorgos, M; Pandolfi, PP; Sridhar, S Nanoformulation of the PARP inhibitor olaparib enables radiosensitization of a radiation-resistant prostate cancer model Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. E595, 2016. Belz, J; Ojo, Castilla N; Kumar, R; Cormack, RA; Makrigiorgos, M; Sridhar, S; D'Amico, AV; Nguyen, PL Docetaxel-Loaded Brachytherapy Spacers for Combined Chemoradiation Therapy in Prostate Cancer Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. S109, 2016. Kunjachan, S; Detappe, A; Kumar, R; Sridhar, S; Makrigiorgos, M; Berbeco, RI Nanoparticle-Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. S97, 2016. Reyes, Gino Karlo Lapitan Delos; de Ven, Anne Van; Soheilian, Rasam; Sridhar, Srinivas; Erb, Randall; Fenniri, Hicham Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the Treatment of Pancreatic Cancer Journal Article In: 2016. van de Ven, Anne L; Shann, Mary H; Sridhar, Srinivas Essential components of a successful doctoral program in nanomedicine Journal Article In: International journal of nanomedicine, vol. 10, pp. 23, 2015. Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jadhav, Tej; Fowle, William; Niedre, Mark; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy Journal Article In: International Journal of Radiation Oncology* Biology* Physics, vol. 91, no. 2, pp. 393–400, 2015. Tangutoori, Shifalika; Baldwin, Paige; Sridhar, Srinivas PARP inhibitors: A new era of targeted therapy Journal Article In: Maturitas, vol. 81, no. 1, pp. 5–9, 2015. Cheng, Ming; Homayoni, Homa; Kumar, Rajiv; Sridhar, Srinivas; Webster, Thomas; Ebong, Eno Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake Journal Article In: The FASEB Journal, vol. 29, no. 1_supplement, pp. LB168, 2015. Cifter, G; Sajo, E; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, G; Ngwa, W MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles Journal Article In: Medical physics, vol. 42, no. 6Part29, pp. 3565–3565, 2015. Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration Proceedings Article In: 2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC), pp. 1–2, IEEE 2015. Ozturk, Birol; de-Luna-Bugallo, Andres; Panaitescu, Eugen; Chiaramonti, Ann N; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Kharche, Neerav; Yavuzcetin, Ozgur; Alnaji, Majed; others, Atomically thin layers of B--N--C--O with tunable composition Journal Article In: Science advances, vol. 1, no. 6, pp. e1500094, 2015. Kumar, Rajiv; Belz, Jodi; Korideck, Houari; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models Miscellaneous 2015. Tangutoori, Shifalika; Bladwin, Paige; Ohman, Anders; Korideck, Houari; Cormack, Robert; Dinulescu, Daniela; Makrigiorgos, Mike; Sridhar, Srinivas NanoPARPi inhibitors for ovarian and prostate cancer therapy Miscellaneous 2015. Tangutoori, Shifalika; Baldwin, Paige; Medina, Jamie; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models Miscellaneous 2015. Kunjachan, Sijumon; Detappe, Alexandre; Kumar, Rajiv; Ireland, Thomas; Cameron, Lisa; Biancur, Douglas E; Motto-Ros, Vincent; Sancey, Lucie; Sridhar, Srinivas; Makrigiorgos, Mike G; others, Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy Journal Article In: Nano letters, vol. 15, no. 11, pp. 7488–7496, 2015. Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration Proceedings Article In: TISSUE ENGINEERING PART A, pp. S307–S307, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015. Cheng, MJ; Kumar, R; Sridhar, S; Webster, TJ; Ebong, EE Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells Proceedings Article In: TISSUE ENGINEERING PART A, pp. S401–S401, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015. Ozturk, Birol; Yavuzcetin, Ozgur; Sridhar, Srinivas A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications Journal Article In: International Journal of Optics, vol. 2015, 2015. Baldwin, Paige; Shanmugam, Ilanchezhian; Tangutoori, Shifalika; Ohman, Anders; Dinulescu, Daniela; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy Miscellaneous 2015. Belz, Jodi; Liby, Karen; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne L; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer Miscellaneous 2015. Kumar, Rajiv; Belz, Jodi; Shanmugam, Ilanchezhian; Ngwa, Wilfred; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy Miscellaneous 2015. TANGUTOORI, Shifalika; Sridhar, Srinivas Nanoparticle drug delivery system and method of treating cancer and neurotrauma Miscellaneous 2015. Clarke, Nicole; Biscocho, Jewison; Kwei, Kevin A; Davidson, Jean M; Sridhar, Sushmita; Gong, Xue; Pollack, Jonathan R Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer Journal Article In: PloS one, vol. 10, no. 11, 2015. Debay, Ann Chiaramonti C; Ozturk, Birol; de Luna Bugallo, Andres; Panaitescu, Eugene; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Yavuzcetin, Ozgur; Alnaji, Majed; Zhao, Yongui; others, Atomically thin layers of BNCO with tuneable composition Technical Report 2015. Teh, James; Hanson, Robert; Sridhar, Srinivas Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics Proceedings Article In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2015. Wang, Haotian; Kumar, Rajiv; Nagesha, Dattatri; Jr, Richard I Duclos; Sridhar, Srinivas; Gatley, Samuel J Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse Journal Article In: Nuclear medicine and biology, vol. 42, no. 1, pp. 65–70, 2015. Gharagouzloo, Codi Amir; McMahon, Patrick N; Sridhar, Srinivas Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences Journal Article In: Magnetic resonance in medicine, vol. 74, no. 2, pp. 431–441, 2015. Sinha, Neeharika; Cifter, Gizem; Sajo, Erno; Kumar, Rajiv; Sridhar, Srinivas; Nguyen, Paul L; Cormack, Robert A; Makrigiorgos, Mike G; Ngwa, Wilfred Brachytherapy application with in situ dose painting administered by gold nanoparticle eluters Journal Article In: International Journal of Radiation Oncology* Biology* Physics, vol. 91, no. 2, pp. 385–392, 2015. Cifter, G; Sajo, E; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, G; Ngwa, W Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles: MO-FG-BRA-05 Journal Article In: Medical Physics, vol. 42, no. 6, 2015. Geilich, Benjamin M; van de Ven, Anne L; Singleton, Gloria L; Sepulveda, Liuda J; Sridhar, Srinivas; Webster, Thomas J Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections Journal Article In: Nanoscale, vol. 7, no. 8, pp. 3511–3519, 2015. Tangutoori, S; Korideck, H; Kumar, R; Sridhar, S; Makrigiorgos, G; Cormack, R WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres Journal Article In: Medical Physics, vol. 41, no. 6Part30, pp. 518–518, 2014. Petrov, Yury; Nador, Jeffrey; Hughes, Christopher; Tran, Stanley; Yavuzcetin, Ozgur; Sridhar, Srinivas Ultra-dense EEG sampling results in two-fold increase of functional brain information Journal Article In: Neuroimage, vol. 90, pp. 140–145, 2014. Belz, Jodi; Kumar, Rajiv; Markovic, Stacey; Niedre, Mark; Sridhar, Srinivas; Nguyen, Paul; Damico, Anthony; Makrigiorgos, Mike; Cormack, Robert Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants Proceedings Article In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014. Sridhar, S; Tangutoori, S; Baldwin, P 361 Nanoformulations of the PARP inhibitors olaparib and BMN 673 for cancer nanotherapy Journal Article In: European Journal of Cancer, vol. 50, pp. 116, 2014. Berbeco, RI; Korideck, H; Kumar, R; Sridhar, S; Detappe, A; Ngwa, W; Makrigiorgos, M Targeted gold nanoparticles as vascular disrupting agents during radiation therapy Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 90, no. 1, pp. S198, 2014. Gharagouzloo, Codi; McMahon, Patrick N; Sridhar, Srinivas UTE angiography with ferumoxytol Proceedings Article In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014. Berbeco, R; Korideck, H; Kumar, R; Sridhar, S; Makrigiorgos, M 20: Targeted Gold Nanoparticles as Vascular Disrupting Agents during Radiotherapy Journal Article In: Radiotherapy and Oncology, vol. 110, pp. S10–S11, 2014. Navarro, Gemma; Essex, Sean; Sawant, Rupa R; Biswas, Swati; Nagesha, Dattatri; Sridhar, Srinivas; de ILarduya, Conchita Tros; Torchilin, Vladimir P Phospholipid-modified polyethylenimine-based nanopreparations for siRNA--mediated gene silencing: Implications for transfection and the role of lipid components Journal Article In: Nanomedicine: Nanotechnology, Biology and Medicine, vol. 10, no. 2, pp. 411–419, 2014. Ngwa, Wilfred; Kumar, Rajiv; Sridhar, Srinivas; Korideck, Houari; Zygmanski, Piotr; Cormack, Robert A; Berbeco, Ross; Makrigiorgos, Mike G Targeted radiotherapy with gold nanoparticles: current status and future perspectives Journal Article In: Nanomedicine, vol. 9, no. 7, pp. 1063–1082, 2014. Faegh, Samira; Jalili, Nader; Sridhar, Srinivas Ultrasensitive piezoelectric-based microcantilever biosensor: Theory and experiment Journal Article In: IEEE/ASME Transactions on Mechatronics, vol. 20, no. 1, pp. 308–312, 2014. Belz, Jodi E; Ngwa, Wilfred; Korideck, Houari; Cormack, Robert A; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas; Kumar, Rajiv Multifunctional nanoparticles in radiation oncology: an emerging paradigm Book Section In: The Science and Function of Nanomaterials: From Synthesis to Application, pp. 75–106, American Chemical Society, 2014. Sridhar, S; Kumar, Rajesh P; Ramanaiah, KV Wavelet Transform Techniques for Image Compression-An Evaluation Journal Article In: International journal of image, graphics and signal processing, vol. 6, no. 2, pp. 54, 2014. Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Niedre, Mark; Ngwa, Wilfred; Korideck, Houari; Cormack, Robert; Nguyen, Paul; D'Amico, Anthony; Makrigiorgos, Mike; others, Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy Miscellaneous 2014. Tangutoori, Shifalika; Baldwin, Paige; Korideck, Houari; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas Nanoformulations of PARP inhibtors for cancer therapy Miscellaneous 2014. Khabiry, Masoud; Jalili, Nader; Sridhar, Srinivas Automated cell counting method for microgroove based microfluidic device Proceedings Article In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014. van de Ven, Anne L; Geilich, Benjamin; Gharagouzloo, Codi; Barlow, Jacob; Webster, Thomas; Sridhar, Srinivas Polymersomes for image-guided therapy Proceedings Article In: 2014 40th Annual Northeast Bioengineering Conference (NEBEC), pp. 1–2, IEEE 2014. Ngwa, W; Altundal, Y; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, M Radiation Therapy Biomaterials for Response Assessment and Nodal Detection (Brand) Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 90, no. 1, pp. S856, 2014. Cormack, R; Ngwa, W; Tangutoori, S; Rajiv, K; Sridhar, S; Makrigiorgos, G SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy Journal Article In: Medical Physics, vol. 41, no. 6Part22, pp. 389–390, 2014. Petrov, Yury; Sridhar, Srinivas Electric Field Encephalography: Electric fields and their application to functional brain imaging. Journal Article In: 2013. Yavuzcetin, O; Perry, Nicholas R; Malley, Sean T; Dally, Rebecca L; Novikov, Herman P; Ozturk, Birol; Sridhar, Srinivas Fabrication and characterization of single mode annealed proton exchanged waveguides in-x-cut lithium niobate Journal Article In: Optical Materials, vol. 36, no. 2, pp. 372–375, 2013. Gharagouzloo, CA; Madi, S; Seethamraju, RT; Harisinghani, M; Sridhar, S Ultrashort TE imaging with SPIONs: bright prospects for in vivo applications Proceedings Article In: JOURNAL OF NUCLEAR MEDICINE, pp. 9–9, SOC NUCLEAR MEDICINE INC 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA 2013. Gharagouzloo, Codi; Jillela, Manasa; Kumar, Rajiv; Nagesha, Dattatri; Sridhar, Srinivas Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. Miscellaneous 2013. Ngwa, Wilfred; Korideck, Houari; Kassis, Amin I; Kumar, Rajiv; Sridhar, Srinivas; Makrigiorgos, Mike G; Cormack, Robert A In vitro radiosensitization by gold nanoparticles during continuous low-dose-rate gamma irradiation with I-125 brachytherapy seeds Journal Article In: Nanomedicine: Nanotechnology, Biology and Medicine, vol. 9, no. 1, pp. 25–27, 2013. Rivera-Chacon, DM; Alvarado-Velez, M; Acevedo-Morantes, CY; Singh, SP; Gultepe, E; Nagesha, D; Sridhar, S; Ramirez-Vick, JE Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces Journal Article In: Journal of biomedical nanotechnology, vol. 9, no. 6, pp. 1092–1097, 2013. Faegh, Samira; Jalili, Nader; Sridhar, Srinivas A self-sensing piezoelectric microcantilever biosensor for detection of ultrasmall adsorbed masses: theory and experiments Journal Article In: Sensors, vol. 13, no. 5, pp. 6089–6108, 2013. Chapman, Sandra; Dobrovolskaia, Marina; Farahani, Keyvan; Goodwin, Andrew; Joshi, Amit; Lee, Hakho; Meade, Thomas; Pomper, Martin; Ptak, Krzysztof; Rao, Jianghong; others, Nanoparticles for cancer imaging: The good, the bad, and the promise Journal Article In: Nano today, vol. 8, no. 5, pp. 454–460, 2013. Kumar, Rajiv; Korideck, Houari; Ngwa, Wilfred; Berbeco, Ross I; Makrigiorgos, Mike G; Sridhar, Srinivas Third generation gold nanoplatform optimized for radiation therapy Journal Article In: Translational cancer research, vol. 2, no. 4, 2013. Petrov, Yury; Sridhar, Srinivas Electric field encephalography as a tool for functional brain research: a modeling study Journal Article In: PloS one, vol. 8, no. 7, 2013. Faegh, Samira; Jalili, Nader; Yavuzcetin, Ozgur; Nagesha, Dattatri; Kumar, Rajiv; Sridhar, Srinivas A cost-effective self-sensing biosensor for detection of biological species at ultralow concentrations Journal Article In: Journal of Applied Physics, vol. 113, no. 22, pp. 224905, 2013. Ngwa, W; Korideck, H; Kumar, R; Sridhar, S; David, K; Paul, N; Berbeco, R; Cormack, R; Makrigiorgos, G Toward Customizable Radiation Therapy Enhancement (CuRE) With Gold Nanoparticles Released, In Situ, From Gold-Loaded Brachytherapy Spacers Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 87, no. 2, pp. S151, 2013. Tangutoori, Shifalika; Korideck, Houari; Makrigiorgos, Mike; Cormack, Robert; Sridhar, Srinivas Abstract A81: A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer. Miscellaneous 2013. Kumar, Rajiv; Kulkarni, Apurva; Nabulsi, Jude; Nagesha, Dattatri K; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas Facile synthesis of PEGylated PLGA nanoparticles encapsulating doxorubicin and its in vitro evaluation as potent drug delivery vehicle Journal Article In: Drug delivery and translational research, vol. 3, no. 4, pp. 299–308, 2013. Teh, James L; Hanson, Robert N; Sridhar, Srinivas Synthesis and characterization of Arg-Gly-Asp (RGD) peptidomimetics functionalized onto gold nanoparticles Proceedings Article In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2013. Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jadhav, Tej; Nguyen, Paul; Niedre, Mark; DAmico, Anthony; Makrigiorgos, Mike; Cormack, Robert; Sridhar, Srinivas Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. Miscellaneous 2013. Kumar, Rajiv; Belz, Jodi E; Markovic, Stacey; Korideck, Houari; Ngwa, Wilfred F; Niedre, Mark; Berbeco, Ross I; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas Abstract A82: Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants. Miscellaneous 2013. Sridhar, Srinivas; Dokmeci, Mehmet; Mosallaei, Hossein; Menon, Latika; Sokoloff, Jeffrey; Heiman, Don Metamaterials and Conformal Antenna Technologies Technical Report DTIC Document 2013. Campbell, Robert B; Sridhar, Srinivas Magnetic nanoplatforms for theranostic and multi-modal imaging applications Miscellaneous 2013, (US Patent App. 13/583,616). Anderson, D; Archakov, A; Avgoustakis, K; Baumgartner, A; Bawa, R; Bernardo, M; Biricova, V; Brayner, R; Brechbiel, MW; Buse, J; others, Our thanks to all those who have helped with this issue of Nanomedicine. Listed below are authors, referees and others who have kindly given their time, effort and expertise; their generosity has helped establish this publication. Journal Article In: 2012. Kumar, Rajiv; Patel, Janki; Korideck, Houari; Berbeco, Ross I; Makrigiorgos, Mike G; Sridhar, Srinivas Comprehensive evaluation of PEGylated gold nanorods for two photon photoluminescence image guided radiation therapy enhancement Miscellaneous 2012. Kumar, Rajiv; Kulkarni, Apurva; Nagesha, Dattatri; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas Nanocoated brachytherapy spacers eluting radiosensitizers for biological in situ image-guided radiation therapy of prostate cancer Miscellaneous 2012. Kumar, Rajiv; Kulkarni, Apurva; Nagesha, Dattatri K; Sridhar, Srinivas In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer Journal Article In: Theranostics, vol. 2, no. 7, pp. 714, 2012. Berbeco, Ross I; Korideck, Houari; Ngwa, Wilfred; Kumar, Rajiv; Patel, Janki; Sridhar, Srinivas; Johnson, Sarah; Price, Brendan D; Kimmelman, Alec; Makrigiorgos, Mike G DNA damage enhancement from gold nanoparticles for clinical MV photon beams Journal Article In: Radiation research, vol. 178, no. 6, pp. 604–608, 2012. Yavuzcetin, Ozgur; Novikov, Herman P; Dally, Rebecca L; Malley, Sean T; Perry, Nicholas R; Ozturk, Birol; Sridhar, Srinivas Photonic crystal fabrication in lithium niobate via pattern transfer through wet and dry etched chromium mask Journal Article In: Journal of Applied Physics, vol. 112, no. 7, pp. 074303, 2012. Berbeco, R; Korideck, H; Ngwa, W; Kumar, R; Patel, J; Sridhar, S; Johnson, S; Price, B; Kimmelman, A; Makrigiorgos, M TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations Journal Article In: Medical Physics, vol. 39, no. 6Part23, pp. 3900–3901, 2012. Ngwa, W; Korideck, H; Kimmelman, A; Kassis, AI; Kumar, R; Sridhar, S; Makrigiorgos, M; Cormack, RA In vitro dose enhancement from gold nanoparticles during low-dose-rate gamma irradiation with I-125 brachytherapy seeds Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 84, no. 3, pp. S134, 2012. Cormack, R; Nguyen, P; D'Amico, AV; Sridhar, S; Makrigiorgos, GM Locally Drug Enhanced Brachytherapy: A Comparison of 2 Approaches Based on Biologically Effective Dose Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 84, no. 3, pp. S854–S855, 2012. D.Plouffea, Brian; K.Nagesha, Dattatri; S.DiPietro, Robert; Sridhar, Srinvas; Heimand, Don; K.Murthya, Shashi; H.Lewisa, Lewis Thermomagnetic determination of Fe3O4 magnetic nanoparticle diameters for biomedical applications Journal Article In: Journal of Magnetism and Magnetic Materials, vol. 323, no. 17, pp. 2310-2317, 2011. Makrigiorgos, Robert A. Cormack; Paul L. Nguyen; Anthony V. D'Amico; Sri Sridhar; Mike Optimal drug release schedule for in-situ radiosensitization of image guided permanent prostate implants Journal Article In: Proceedings Volume 7964, Medical Imaging 2011: Visualization, Image-Guided Procedures, and Modeling, vol. 7964, no. 2011, 2011. Sridhar, Srinivas; Gultepe, Evin; Nagesha, Dattatri Large scale nanoelement assembly method for making nanoscale circuit interconnects and diodes Miscellaneous 2011, (US Patent App. 12/936,938). Sridhar, Srinivas; Campbell, Robert; Nagesha, Dattatri; Gultepe, Evin Magnetic nanoplatforms for tumor targeting, imaging and energy delivery Miscellaneous 2011. Lu, WT; Huang, YJ; Sridhar, S Slow light using negative metamaterials Proceedings Article In: Active Photonic Materials IV, pp. 80951D, International Society for Optics and Photonics 2011. Savo, Salvatore; Casse, BDF; Lu, Wentao; Sridhar, Srinivas Observation of slow-light in a metamaterials waveguide at microwave frequencies Journal Article In: Applied Physics Letters, vol. 98, no. 17, pp. 171907, 2011. Ye, Yong-Hong; Huang, YJ; Lu, WT; Casse, BDF; Xiao, D; Bennett, SP; Heiman, D; Menon, L; Sridhar, S Tuning the optical properties of metamaterials based on gold nanowire arrays embedded in alumina Journal Article In: Optical Materials, vol. 33, no. 11, pp. 1667–1670, 2011. Yavuzcetin, Ozgur; Ozturk, Birol; Xiao, Dong; Sridhar, Srinivas Conicity and depth effects on the optical transmission of lithium niobate photonic crystals patterned by focused ion beam Journal Article In: Optical Materials Express, vol. 1, no. 7, pp. 1262–1271, 2011. Casse, BDF; Lu, WT; Huang, YJ; Sridhar, S Robust method to determine the resolution of a superlens by analyzing the near-field image of a two-slit object Journal Article In: arXiv preprint arXiv:1105.0182, 2011. Alvarado-Velez, Melissa; Rivera-Chacon, Delva M; Acevedo-Morantes, Claudia Y; Menon, Latika; Nagesha, Dattatri; Gultepe, Evin; Sridhar, Srinivas; Ramirez-Vick, Jaime E; Singh, Surinder P Effects of fibronectin and vitronectin on human fetal osteoblast cell attachment and proliferation on nanostructured titania surfaces Proceedings Article In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2011. Sridhar, Srinivas; Nagesha, Dattatri; Tada, Dayane; Kumar, Rajiv; Makrigiorgos, Mike G; Cormack, Robert Radio-sensitizer eluting nanoporous coatings on fiducials markers: Biological in-situ dose-painting for IGRT Miscellaneous 2011. Savo, Salvatore; Lu, Wentao T; Casse, Bernard Didier F; Sridhar, Srinivas SLOW LIGHT IN NEGATIVE PERMEABILITY METAMATERIAL WAVEGUIDES Book Section In: Selected Topics In Photonic Crystals And Metamaterials, pp. 373–387, 2011. Casse, Bernard Didier F; Sridhar, Srinivas Superresolution imaging and superfocusing with negative-index metamaterials Journal Article In: 2010. Gultepe, Evin; Nagesha, Dattatri; Sridhar, Srinivas; Amiji, Mansoor Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices Journal Article In: Advanced drug delivery reviews, vol. 62, no. 3, pp. 305–315, 2010. Casse, BDF; Lu, WT; Huang, YJ; Gultepe, E; Menon, L; Sridhar, S Super-resolution imaging using a three-dimensional metamaterials nanolens Journal Article In: Applied Physics Letters, vol. 96, no. 2, pp. 023114, 2010. Stambaugh, C; Tada, D; Nagesha, D; Jost, E; Levy, C; Cormack, RA; Makrigiorgos, M; Sridhar, S WE-E-204B-02: Release Kinetics of Radio-Sensitizers from Nanoporous Coatings on Gold Fiducials: Biological In-Situ Dose-Painting for IGRT Journal Article In: Medical Physics, vol. 37, no. 6Part13, pp. 3437–3438, 2010. Cormack, Robert A; Nagesha, Dattatri; Gultepe, Evin; Nguyen, Paul; D'Amico, Anthony V; Sridhar, Srinivas; Makrigiorgos, Mike Drug Eluting Brachytherapy Spacers: A Potential for Biologically-Enhanced Brachytherapy Journal Article In: Brachytherapy, vol. 9, pp. S48–S49, 2010. Lu, WT; Huang, YJ; Casse, BDF; Banyal, RK; Sridhar, S Storing light in active optical waveguides with single-negative materials Journal Article In: Applied Physics Letters, vol. 96, no. 21, pp. 211112, 2010. Gultepe, Evin; Reynoso, Francisco J; Jhaveri, Aditi; Kulkarni, Praveen; Nagesha, Dattatri; Ferris, Craig; Harisinghani, Mukesh; Campbell, Robert B; Sridhar, Srinivas Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution Journal Article In: Nanomedicine, vol. 5, no. 8, pp. 1173–1182, 2010. Makrigiorgos, M; Sridhar, S; D’Amico, A; Nguyen, P; Cormack, R 40 poster: Biological In-Situ Dose Painting for IGRT (BIS-IGRT) by Use of Drug-Loaded Implantable Fiducials and Spacers Journal Article In: Radiotherapy and Oncology, vol. 94, pp. S18, 2010. Gultepe, Evin; Nagesha, Dattatri; Casse, Bernard DF; Banyal, Ravinder; Fitchorov, Trifon; Karma, Alain; Amiji, Mansoor; Sridhar, Srinivas Sustained Drug Release from Non-eroding Nanoporous Templates Journal Article In: Small, vol. 6, no. 2, pp. 213–216, 2010. Nagesha, DK; Tada, DB; Stambaugh, CKK; Gultepe, E; Jost, E; Levy, CO; Cormack, R; Makrigiorgos, GM; Sridhar, S Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT) Journal Article In: Physics in Medicine & Biology, vol. 55, no. 20, pp. 6039, 2010. Tada, Dayane B; Singh, Surinder; Nagesha, Dattatri; Jost, Evan; Levy, Craig O; Gultepe, Evin; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas Chitosan film containing poly (D, L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release Journal Article In: Pharmaceutical research, vol. 27, no. 8, pp. 1738–1745, 2010. Lu, WT; Sridhar, S Slow light, open-cavity formation, and large longitudinal electric field on a slab waveguide made of indefinite permittivity metamaterials Journal Article In: Physical Review A, vol. 82, no. 1, pp. 013811, 2010. Cormack, Robert A; Sridhar, Srinivas; Suh, Warren W; D'Amico, Anthony V; Makrigiorgos, Mike G Biological in situ dose painting for image-guided radiation therapy using drug-loaded implantable devices Journal Article In: International Journal of Radiation Oncology* Biology* Physics, vol. 76, no. 2, pp. 615–623, 2010. Lu, Wentao T; Sridhar, Srinivas; Vodo, Plarenta; Parimi, Patanjali; Huang, Yongjian Photonic crystal devices using negative refraction Miscellaneous 2010, (US Patent 7,808,716). Cormack, R; Nguyen, P; Amico, A D”; Sridhar, S; Makrigiorgos, M MO-FF-A1-01: Optimal Schedule for Localized Radio-Sensitization of 125I Prostate Implants Journal Article In: Medical Physics, vol. 37, no. 6Part26, pp. 3361–3361, 2010. Casse, BDF; Lu, WT; Huang, YJ; Gultepe, E; Menon, L; Sridhar, S Beating the diffraction limit using a 3D nanowires metamaterials nanolens Proceedings Article In: Frontiers in Optics, pp. FWO3, Optical Society of America 2010. Reynoso, F; Gultepe, E; Jhaveri, A; Kulkarni, P; Gershman, B; Ferris, C; Campbell, R; Harisinghani, M; Sridhar, S TH-D-201C-08: Multi-Modal MRI SPECT and CT Imaging of Theranostic Nanoplatforms Journal Article In: Medical Physics, vol. 37, no. 6Part8, pp. 3470–3470, 2010. Casse, Bernard Didier Frederic; Lu, Wentao; Huang, Yongjian; Gultepe, Evin; Menon, Latika; Sridhar, Srinivas Superresolution Imaging Using a 3D Nanolens Made Up of Bulk Nanowires Metamaterials Journal Article In: Bulletin of the American Physical Society, vol. 55, 2010. Casse, Bernard Didier Frederic; Lu, Wentao; Huang, Yongjian; Gultepe, Evin; Menon, Latika; Sridhar, Srinivas Superresolution Imaging Using a 3D Nanolens Made Up of Bulk Nanowires Metamaterials Proceedings Article In: APS Meeting Abstracts, 2010. Casse, BDF; Lu, WT; Banyal, RK; Huang, YJ; Selvarasah, S; Dokmeci, MR; Perry, CH; Sridhar, S Imaging with subwavelength resolution by a generalized superlens at infrared wavelengths Journal Article In: Optics letters, vol. 34, no. 13, pp. 1994–1996, 2009. Lu, Wentao T; Savo, Savatore; Casse, Didier B F; Sridhar, Srinivas Slow microwave waveguide made of negative permeability metamaterials Journal Article In: Microwave and Optical Technology Letters, vol. 51, no. 11, pp. 2705–2709, 2009. Nagesha, Dattatri K; Plouffe, Brian D; Phan, Minh; Lewis, Laura H; Sridhar, Srinivas; Murthy, Shashi K Functionalization-induced improvement in magnetic properties of Fe 3 O 4 nanoparticles for biomedical applications Journal Article In: Journal of Applied Physics, vol. 105, no. 7, pp. 07B317, 2009. Sawant, Rishikesh M; Sawant, Rupa R; Gultepe, Evin; Nagesha, Dattatri; Papahadjopoulos-Sternberg, Brigitte; Sridhar, Srinivas; Torchilin, Vladimir P Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles Journal Article In: Journal of Nanoparticle Research, vol. 11, no. 7, pp. 1777, 2009. Lu, WT; Sridhar, S Slow light, open cavity formation, and large longitudinal electric field on slab waveguide made of indefinite-index metamaterials Journal Article In: arXiv preprint arXiv:0902.4482, 2009. Sridhar, S Nanoplatforms for Nanomedicine Journal Article In: 2009. Makrigiorgos, M; Sridhar, S; Suh, W; D'Amico, A; Cormack, R Biological In Situ Dose-painting for Image-guided Radiation Therapy using Drug-loaded Implantable Devices Journal Article In: International Journal of Radiation Oncology• Biology• Physics, vol. 75, no. 3, pp. S711–S712, 2009. Cormack, RA; Sridhar, S; Nagesha, D; Gultepe, E; Suh, W; D'Amico, AV; Makrigiorgos, M TH-D-210A-06: Drug Eluting Implanted Devices to Increase Biologic Effective Dose in Image Guided Radiation Therapy Journal Article In: Medical Physics, vol. 36, no. 6Part28, pp. 2819–2819, 2009. Casse, Bernard Didier; Lu, Wentao T; Huang, Yongjian; Sridhar, Srinivas Metallic Nanolens and III-V Nano-Optical Metamaterials Lenses for Subwavelength Imaging and Optoelectronics Applications Proceedings Article In: Optics and Photonics for Advanced Energy Technology, pp. ThC4, Optical Society of America 2009. Patel, Yogesh; Saha, Sucharita; DiMarzio, Charles; O'Malley, D; Nagesha, Dattatri; Sridhar, Srinivas Metallic nanoparticles for biomedical imaging Proceedings Article In: 2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro, pp. 759–762, IEEE 2009. Sridhar, Srinivas; Lu, Wentao Anisotropic metal-dielectric metamaterials for broadband all-angle negative refraction and superlens imaging Miscellaneous 2009, (US Patent App. 12/220,445). Menon, L; Lu, W; Friedman, A; Bennett, S; Heiman, D; Sridhar, S Negative Index Metamaterials Based on Metal Nanowire Arrays Electrodeposited in Nanoporous Alumina Templates Journal Article In: 2008. Lu, WT; Sridhar, S Electronic structure: Wide-band, narrow-band, and strongly correlated systems-Superlens imaging theory for anisotropic nanostructured metamaterials with broadband all-angle negative refraction Journal Article In: Physical Review B Condensed Matter And Materials Physics, vol. 78, no. 23, pp. 233101, 2008. Lu, WT; Sridhar, S Superlens imaging theory for anisotropic nanostructured metamaterials with broadband all-angle negative refraction Journal Article In: Physical Review B, vol. 77, no. 23, pp. 233101, 2008. Banyal, Ravinder; Casse, BDF; Lu, WT; Huang, YJ; Selvarasah, S; Dokmeci, M; Perry, CH; Sridhar, S Experimental realization of a generalized superlens using negative refraction at infrared wavelengths Proceedings Article In: APS Meeting Abstracts, 2008.@misc{baldwin2023nanoencapsulated,
title = {Nanoencapsulated combination drug formulations},
author = {Paige Baldwin and Srinivas Sridhar and Bijay Singh},
year = {2023},
date = {2023-05-01},
note = {US Patent 11,648,211},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{sridhar2023true,
title = {True superconductivity at near ambient temperature has not been confirmed by Dasenbrock-Gammon, et. al. Nature (2023)},
author = {Srinivas Sridhar},
year = {2023},
date = {2023-01-01},
journal = {arXiv preprint arXiv:2303.05987},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{yang2023sustained,
title = {Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer},
author = {Shicheng Yang and Allen Green and Needa Brown and Alexis Robinson and Merline Senat and Bryanna Testino and Daniela M Dinulescu and Srinivas Sridhar},
year = {2023},
date = {2023-01-01},
journal = {Frontiers in Oncology},
volume = {13},
pages = {1175617},
publisher = {Frontiers},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{sridhar2023trueb,
title = {True superconductivity at near ambient temperature has not been confirmed by Dasenbrock-Gammon et al. Nature, volume 615, pages 244–250 (2023)},
author = {Srinivas Sridhar},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Journal of Physics and Chemistry of Solids},
pages = {111381},
publisher = {Pergamon},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{kunjachan2022nanoparticle,
title = {Nanoparticle Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy (Retraction of Vol 15, Pg 7488, 2015)},
author = {Sijumon Kunjachan and Alexandre Detappe and Rajiv Kumar and Thomas Ireland and Lisa Cameron and Douglas E Biancur and Vincent Motto-Ros and Lucie Sancey and Srinivas Sridhar and G Mike Makrigiorgos and others},
year = {2022},
date = {2022-01-01},
publisher = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{thong2022multifunctional,
title = {Multifunctional nanocarriers of Fe3O4@ PLA-PEG/curcumin for MRI, magnetic hyperthermia and drug delivery},
author = {Phan Quoc Thong and Le Thi Thu Huong and Nguyen Dac Tu and Hoang Thi My Nhung and Lam Khanh and Do Hung Manh and Pham Hong Nam and Nguyen Xuan Phuc and Javier Alonso and Ju Qiao and others},
year = {2022},
date = {2022-01-01},
journal = {Nanomedicine},
number = {0},
publisher = {Future Medicine Ltd London, UK},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{rodell2021quantification,
title = {Quantification of cellular drug biodistribution addresses challenges in evaluating in vitro and in vivo encapsulated drug delivery},
author = {Christopher B Rodell and Paige Baldwin and Bianca Fernandez and Ralph Weissleder and Srinivas Sridhar and John Matthew Dubach},
year = {2021},
date = {2021-01-01},
journal = {Advanced therapeutics},
volume = {4},
number = {3},
pages = {2000125},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{zhang2021sustained,
title = {Sustained, local delivery of the PARP inhibitor talazoparib prevents the development of mammary gland hyperplasia in BRCA1-deficient mice},
author = {Di Zhang and Bijay Singh and Jessica Moerland and Owen Mitchell and Lizbeth Lockwood and Sarah Carapellucci and Srinivas Sridhar and Karen T Liby},
year = {2021},
date = {2021-01-01},
journal = {Scientific Reports},
volume = {11},
number = {1},
pages = {1234},
publisher = {Nature Publishing Group UK London},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{yang2021recent,
title = {Recent developments in nanomedicine for pediatric cancer},
author = {Shicheng Yang and Mia Wallach and Apurva Krishna and Raushan Kurmasheva and Srinivas Sridhar},
year = {2021},
date = {2021-01-01},
journal = {Journal of Clinical Medicine},
volume = {10},
number = {7},
pages = {1437},
publisher = {MDPI},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{timms2021ferumoxytol,
title = {Ferumoxytol-enhanced ultrashort TE MRA and quantitative morphometry of the human kidney vasculature},
author = {Liam Timms and Tianyi Zhou and Yue Lyu and Ju Qiao and Vishala Mishra and Rita Maria Lahoud and Gayatri Veeramani Jayaraman and Andrew S Allegretti and David Drew and Ravi T Seethamraju and others},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Abdominal Radiology},
volume = {46},
pages = {3288–3300},
publisher = {Springer US},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{versek2021portable,
title = {Portable diagnostic system for age-related macular degeneration screening using visual evoked potentials},
author = {Craig Versek and S Mohammad Ali Banijamali and Peter Bex and Kameran Lashkari and Sagar Kamarthi and Srinivas Sridhar},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {Eye and brain},
pages = {111–127},
publisher = {Taylor & Francis},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cohen2021adapting,
title = {Adapting undergraduate research to remote work to increase engagement},
author = {Susan E Cohen and Sara M Hashmi and A-Andrew D Jones III and Vasiliki Lykourinou and Mary Jo Ondrechen and Srinivas Sridhar and Anne L Ven and Lauren S Waters and Penny J Beuning},
year = {2021},
date = {2021-01-01},
urldate = {2021-01-01},
journal = {The Biophysicist},
volume = {2},
number = {2},
pages = {28–32},
publisher = {Biophysical Society},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{wilfred2020biomaterials,
title = {Biomaterials for combined radiotherapy and immunotherapy of cancer},
author = {NGWA Wilfred and Rajiv Kumar and Gerassimos Makrigiorgos and Srinivas Sridhar and Stephanie Dougan},
year = {2020},
date = {2020-11-01},
urldate = {2020-11-01},
note = {US Patent 10,835,604},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{versek2020portable,
title = {Portable Objective Diagnostics using Visual Evoked Potentials for Age-related Macular Degeneration},
author = {Craig William Versek and Mohammad Ali S Banijamali and Peter J Bex and Kameran Lashkari and Sagar V Kamarthi and Srinivas Sridhar},
year = {2020},
date = {2020-01-01},
journal = {medRxiv},
publisher = {Cold Spring Harbor Laboratory Press},
abstract = {Delayed Dark Adapted vision Recovery (DAR) is a biomarker for Age-related Macular Degeneration (AMD); however, its measurement is burdensome for patients and examiners. We developed a portable, wireless, quick-setup system that employs a headset with a smartphone to deliver and analyze controlled dichoptic photobleach and pattern reversal stimuli, and with custom electroencephalography (EEG) electrodes, to measure objective Dark Adapted Visual Evoked Potentials (DAVEP) at multiple locations of the visual field in one comfortable 20-minute session, without requiring subject reporting. DAVEP responses post photobleach (up to 15 minutes), were measured concurrently in both eyes of 13 patients with AMD and 8 others not diagnosed with AMD. New unexpected features were observed in the DAVEP responses at high latencies to scotopic stimulus intensities. The amplitude recovery of the DAVEP response was significantly delayed in AMD patients compared with controls. We developed DAVEP1 scores, a simple metric for DAR, using it to successfully identify all 100% of AMD subjects and correctly classify 90% of subject eyes. Deficits in DAR in patients with AMD can be identified with this objective VEP based system using the DAVEP1 metric, a promising new objective biomarker for this disease that can be easily tested in a clinic.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cheng2020targeted,
title = {Targeted Intravenous Nanoparticle Delivery: Role of Flow and Endothelial Glycocalyx Integrity},
author = {Ming J Cheng and Ronodeep Mitra and Chinedu C Okorafor and Alina A Nersesyan and Ian C Harding and Nandita N Bal and Rajiv Kumar and Hanjoong Jo and Srinivas Sridhar and Eno E Ebong},
year = {2020},
date = {2020-01-01},
journal = {Annals of Biomedical Engineering},
pages = {1--14},
abstract = {Therapies for atherosclerotic cardiovascular disease should target early disease stages and specific vascular sites where disease occurs. Endothelial glycocalyx (GCX) degradation compromises endothelial barrier function and increases vascular permeability. This initiates pro-atherosclerotic lipids and inflammatory cells to penetrate vessel walls, and at the same time this can be leveraged for targeted drug delivery. In prior cell culture studies, GCX degradation significantly increased endothelial cell uptake of nanoparticle vehicles that are designed for drug delivery, compared to the effects of intact GCX. The present study assessed if the cell culture findings translate to selective nanoparticle uptake in animal vessels. In mice, the left carotid artery (LCA) was partially ligated to disturb blood flow, which induces GCX degradation, endothelial dysfunction, and atherosclerosis. After ligation, the LCA vessel wall exhibited.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{versek2020portableb,
title = {Portable Objective Diagnostics using Visual Evoked Potentials for Age-related Macular Degeneration},
author = {Craig Versek and S Mohammad Ali Banijamali and Peter J Bex and Kameran Lashkari and Sagar V Kamarthi and Srinivas Sridhar},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {medRxiv},
pages = {2020–01},
publisher = {Cold Spring Harbor Laboratory Press},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cheng2020targetedb,
title = {Targeted intravenous nanoparticle delivery: role of flow and endothelial glycocalyx integrity},
author = {Ming J Cheng and Ronodeep Mitra and Chinedu C Okorafor and Alina A Nersesyan and Ian C Harding and Nandita N Bal and Rajiv Kumar and Hanjoong Jo and Srinivas Sridhar and Eno E Ebong},
year = {2020},
date = {2020-01-01},
urldate = {2020-01-01},
journal = {Annals of biomedical engineering},
volume = {48},
pages = {1941–1954},
publisher = {Springer International Publishing},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{mitra2020high,
title = {High fat diet versus disturbed blood flow conditions: Implications for endothelial glycocalyx integrity and pre-atherosclerotic inflammation},
author = {Ronodeep Mitra and Ju Qiao and Sudharsan Madhavan and Gerard O’Neil and Bailey Ritchie and Praveen Kulkarni and Srinivas Sridhar and Anne Ven and Erica Cherry and Craig Ferris and others},
year = {2020},
date = {2020-01-01},
journal = {The FASEB Journal},
volume = {34},
number = {S1},
pages = {1–1},
publisher = {The Federation of American Societies for Experimental Biology},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{schuemann2020roadmap,
title = {Roadmap for metal nanoparticles in radiation therapy: Current status, translational challenges, and future directions},
author = {Jan Schuemann and Alexander F Bagley and Ross Berbeco and Kyle Bromma and Karl T Butterworth and Hilary L Byrne and B Devika Chithrani and Sang Hyun Cho and Jason R Cook and Vincent Favaudon and others},
year = {2020},
date = {2020-01-01},
journal = {Physics in Medicine & Biology},
volume = {65},
number = {21},
pages = {21RM02},
publisher = {IOP Publishing},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{virani2020noninvasive,
title = {Noninvasive imaging of tumor hypoxia after nanoparticle-mediated tumor vascular disruption},
author = {Needa A Virani and Olivia J Kelada and Sijumon Kunjachan and Alexandre Detappe and Jihun Kwon and Jennifer Hayashi and Ana Vazquez-Pagan and Douglas E Biancur and Thomas Ireland and Rajiv Kumar and others},
year = {2020},
date = {2020-01-01},
journal = {Plos one},
volume = {15},
number = {7},
pages = {e0236245},
publisher = {Public Library of Science San Francisco, CA USA},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{mueller2020increased,
title = {Increased carcinoembryonic antigen expression on the surface of lung cancer cells using gold nanoparticles during radiotherapy},
author = {Romy Mueller and Sayeda Yasmin-Karim and Kaylie DeCosmo and Ana Vazquez-Pagan and Srinivas Sridhar and David Kozono and Juergen Hesser and Wilfred Ngwa},
year = {2020},
date = {2020-01-01},
journal = {Physica Medica},
volume = {76},
pages = {236–242},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{zhang2020localized,
title = {Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer},
author = {Di Zhang and Bijay Singh and Jessica Moerland and Owen Mitchell and Lizbeth Lockwood and Sarah Carapellucci and Srinivas Sridhar and Karen Liby},
year = {2020},
date = {2020-01-01},
journal = {Cancer Research},
volume = {80},
number = {16_Supplement},
pages = {12–12},
publisher = {The American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{kunjachan2020author,
title = {Author correction: Selective priming of tumor Blood Vessels by Radiation therapy enhances nanodrug Delivery},
author = {Sijumon Kunjachan and Shady Kotb and Robert Pola and Michal Pechar and Rajiv Kumar and Bijay Singh and Felix Gremse and Reza Taleeli and Florian Trichard and Vincent Motto-Ros and others},
year = {2020},
date = {2020-01-01},
journal = {Scientific Reports},
volume = {10},
number = {1},
pages = {15344},
publisher = {Nature Publishing Group UK London},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{singh2020nanoparticle,
title = {Nanoparticle formulations of poly (ADP-ribose) polymerase inhibitors for cancer therapy},
author = {Bijay Singh and Shicheng Yang and Apurva Krishna and Srinivas Sridhar},
year = {2020},
date = {2020-01-01},
journal = {Frontiers in Chemistry},
volume = {8},
pages = {594619},
publisher = {Frontiers Media SA},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{tangutoori2020nanoparticle,
title = {Nanoparticle drug delivery system and method of treating cancer and neurotrauma},
author = {Shifalika TANGUTOORI and Srinivas Sridhar},
year = {2020},
date = {2020-01-01},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@inproceedings{mitra2020vivo,
title = {In Vivo Flow-Regulated Endothelial Glycocalyx Integrity Leveraged for Targeted Intravenous Nanoparticle Delivery},
author = {Ronodeep Mitra and Ming Cheng and Gerard O'Neil and Praveen Kulkarni and Rajiv Kumar and Srinivas Sridhar and Craig Ferris and James Hamilton and Hanjoong Jo and Eno E Ebong},
year = {2020},
date = {2020-01-01},
booktitle = {2020 Virtual AIChE Annual Meeting},
organization = {AIChE},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@misc{sridhar2019portableb,
title = {Portable brain and vision diagnostic and therapeutic system},
author = {Srinivas Sridhar and Craig Versek and Peter Bex},
year = {2019},
date = {2019-10-01},
abstract = {A portable wireless neuromonitoring device can be used to diagnose and/or treat conditions of the brain and vision system. The device includes a sensor unit mountable on the head of a human subject and capable of recording signals from the brain in EEG and/or EFEG (electric field encephalography) mode, and the device can be used for simultaneous stimulus display and recording with latency of less than 1 millisecond. The device also includes electrodes that allow rapid set-up and measurement with low impedance contact with the scalp. The device can also be used in conjunction with virtual reality or alternate reality environments.},
note = {US Patent App. 16/347,049},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{cheng2019ultrasmall,
title = {Ultrasmall gold nanorods: synthesis and glycocalyx-related permeability in human endothelial cells},
author = {Ming J Cheng and Nandita N Bal and Priya Prabakaran and Rajiv Kumar and Thomas J Webster and Srinivas Sridhar and Eno E Ebong},
year = {2019},
date = {2019-01-01},
journal = {International journal of nanomedicine},
volume = {14},
pages = {319},
publisher = {Dove Press},
abstract = {Clinical data show shed endothelial glycocalyx (GCX) components in blood samples of atherosclerotic patients, linking atherosclerotic development to endothelial GCX integrity. Healthy GCX has pores no> 7 nm, and shed GCX has even larger pores. Therefore, we suggest targeting and treating atherosclerosis-prone blood vessels by using nanoscale vehicles to deliver drugs via the nanoscale GCX as it becomes dysfunctional.
Materials and methods
To test our idea, we investigated permeability of nanoparticles in endothelium, as related to a GCX expression. The present work involves nanorods, which are expected to interact with larger portions of endothelial cell (EC) membranes, due to surface area of the nanorod long axis. Conventional nanorod diameters are orders of magnitude larger than the GCX pore size, so we adapted conventional synthesis methods to fabricate ultrasmall gold nanorods …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Materials and methods
To test our idea, we investigated permeability of nanoparticles in endothelium, as related to a GCX expression. The present work involves nanorods, which are expected to interact with larger portions of endothelial cell (EC) membranes, due to surface area of the nanorod long axis. Conventional nanorod diameters are orders of magnitude larger than the GCX pore size, so we adapted conventional synthesis methods to fabricate ultrasmall gold nanorods …@article{baldwin2019nanoformulation,
title = {Nanoformulation of talazoparib delays tumor progression and ascites formation in a late stage cancer model},
author = {Paige Baldwin and Anders W Ohman and Jamie Edward Medina and Eric Timothy McCarthy and Daniela M Dinulescu and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
journal = {Frontiers in oncology},
volume = {9},
pages = {353},
publisher = {Frontiers},
abstract = {Talazoparib, a potent PARP inhibitor, induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARP inhbitors. We sought to formulate Talazoparib in a nanoparticle delivery system, which allows the drug to be administered intraperitoneally. This was done to specifically target peritoneal dissemination of late stage metastatic ovarian cancer and increase talazoparib’s therapeutic efficacy while minimizing toxic side effects. NanoTalazoparib was developed and characterized with regard to its size, loading, and surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine and human BRCA cell lines and the dose response was compared to Olaparib’s, the currently used PARP inhibitor. Therapeutic efficacy was tested in vivo in a Brca peritoneal cancer model that mimics late stage disseminated disease. NanoTalazoparib has a diameter of about 70 nm with a neutral surface charge and ~75% encapsulation efficiency, which slowly releases the drug over several hours. Dose response analysis indicated that the murine cell lines with conditional BRCA1/2, PTEN, and TP53 deletions had the lowest IC50s. NanoTalazoparib administered on a schedule of three doses weekly slowed disease progression and resulted in significantly less mice with ascites at the end point compared to controls. These results indicate that the slow release nanoformulation, NanoTalazoparib, effectively delivers PARP inhibitor therapy to the peritoneal cavity for …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{versek2019portable,
title = {Portable system for neuro-optical diagnostics using virtual reality display},
author = {Craig Versek and Armen Rissmiller and Anthony Tran and Munish Taya and Kaushik Chowdhury and Peter Bex and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
journal = {Military medicine},
volume = {184},
number = {Supplement_1},
pages = {584--592},
publisher = {Oxford University Press},
abstract = {A new product prototype system for diagnosing vision and neurological disorders, called NeuroDotVR, is described herein: this system utilizes a novel wireless NeuroDot brain sensor [Versek C et al. J Neural Eng. 2018 Aug; 15(4):046027] that quantitatively measures visual evoked potentials and fields resulting from custom visual stimuli displayed on a smartphone housed in a virtual reality headset. The NeuroDot brain sensor is unique in that it can be operated both in regular electroencephalography mode, as well as a new electric field encephalography mode, which yields improvements in signal sensitivity and provides new diagnostic information. Steady state and transient visual evoked potentials and fields using reversing checkerboard stimuli are presented with case studies in amblyopia, glaucoma, and dark adaptation. These preliminary data sets highlight potential clinical applications that may be …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{kelada2019noninvasive,
title = {Noninvasive imaging of tumor hypoxia during radiation-induced tumor vascular disruption},
author = {Olivia J Kelada and Sijumon Kunjachan and Needa A Virani and Alexandre Detappe and Jennifer Hayashi and Thomas Ireland and Douglas E Biancur and Rajiv Kumar and Srinivas Sridhar and Mike Makrigiorgos and others},
year = {2019},
date = {2019-01-01},
publisher = {American Association for Cancer Research},
abstract = {Purpose Tumor vascular targeted gold nanoparticles induce tumor vascular disruption when combined with external beam radiation therapy. Although effective in suppressing tumor growth and improving progression-free survival, tumor hypoxia may be a potential challenge in this anti-vascular therapy. Here, we investigate, the dynamic changes in tumor hypoxia pre- and post-radiation therapy using a gold nanoparticle-based tumor vascular disrupting agent.
Materials and methods 4-6 weeks old female nude-FOXn1 mice were subcutaneously inoculated with human A549 cells (~3×106) into the left flank. Functionalized gold nanoparticles (AuNP) were used to target the tumor blood vessels and tumor vascular disruption was induced via radiation. 10 Gy radiation treatment was delivered using a clinical radiation beam (6 MV) and HypoxiSense680 based in vivo fluorescence imaging was performed to visualize changes in tumor hypoxia at 24 h, 48 h and an extended period of 10 days. Tumor hypoxia was confirmed via immunohistochemistry. Mice were divided into four treatment groups: control, AuNP only, IR only, and AuNP+IR. Following treatment, tumor progression and overall survival was measured. Further analysis of nanoparticle biodistribution and toxicity were accessed using TEM Imaging, IC-PMS, and immunohistochemistry.
Results Longitudinal changes in tumor hypoxia were observed in all radiation-based treatment conditions. Combining gold nanoparticle and radiation resulted in an increase in tumor hypoxia at 48 h (p < 0.05) and a return to baseline in 10 days. In contrast, the ‘radiation only’ group showed an increase in tumor hypoxia by a factor of 0.5 at 48 h post-IR compared to baseline while 10 days later the tumor hypoxia remained stable. Quantitative variation in the hypoxia blood factor, CA9 increased 24 h post IR in the AuNP+IR, followed by a decrease in hypoxic by day 10 in accordance with in vivo imaging data. No change was observed with the IR only group. These findings were confirmed with representative pimonidazole staining that showed an increase in tumor hypoxia a few hours after AuNP+IR treatment. The mean relative reduction in tumor size post-treatment was a factor of 5.2 (p < 0.05) in the AuNP+IR group compared to the control and 3.5 compared to the IR only group, nearly 80 days post-treatment. Overall survival showed an average gain of up to 24 days in the AuNP+IR group compared to all other treatments. Almost 100 days post-treatment, 50% survival was observed in the AuNP+IR group compared to 20% in the IR-only groups (p < 0.05).
Conclusions Noninvasive imaging showed that AuNP+IR results in a transient increase and subsequent decline in mean tumor hypoxia, leading to substantial tumor regression and an overall increase in tumor survival. High radiation-induced vascular damage may lead to better tumor reduction and prolonged survival in the human non-small cell lung cancer model.
Citation Format: Olivia J. Kelada, Sijumon Kunjachan, Needa A. Virani, Alexandre Detappe, Jennifer Hayashi, Thomas Ireland, Douglas E. Biancur, Rajiv Kumar, Srinivas Sridhar, Mike Makrigiorgos, Ross I. Berbeco. Noninvasive imaging of tumor hypoxia during radiation-induced tumor vascular disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 85.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Materials and methods 4-6 weeks old female nude-FOXn1 mice were subcutaneously inoculated with human A549 cells (~3×106) into the left flank. Functionalized gold nanoparticles (AuNP) were used to target the tumor blood vessels and tumor vascular disruption was induced via radiation. 10 Gy radiation treatment was delivered using a clinical radiation beam (6 MV) and HypoxiSense680 based in vivo fluorescence imaging was performed to visualize changes in tumor hypoxia at 24 h, 48 h and an extended period of 10 days. Tumor hypoxia was confirmed via immunohistochemistry. Mice were divided into four treatment groups: control, AuNP only, IR only, and AuNP+IR. Following treatment, tumor progression and overall survival was measured. Further analysis of nanoparticle biodistribution and toxicity were accessed using TEM Imaging, IC-PMS, and immunohistochemistry.
Results Longitudinal changes in tumor hypoxia were observed in all radiation-based treatment conditions. Combining gold nanoparticle and radiation resulted in an increase in tumor hypoxia at 48 h (p < 0.05) and a return to baseline in 10 days. In contrast, the ‘radiation only’ group showed an increase in tumor hypoxia by a factor of 0.5 at 48 h post-IR compared to baseline while 10 days later the tumor hypoxia remained stable. Quantitative variation in the hypoxia blood factor, CA9 increased 24 h post IR in the AuNP+IR, followed by a decrease in hypoxic by day 10 in accordance with in vivo imaging data. No change was observed with the IR only group. These findings were confirmed with representative pimonidazole staining that showed an increase in tumor hypoxia a few hours after AuNP+IR treatment. The mean relative reduction in tumor size post-treatment was a factor of 5.2 (p < 0.05) in the AuNP+IR group compared to the control and 3.5 compared to the IR only group, nearly 80 days post-treatment. Overall survival showed an average gain of up to 24 days in the AuNP+IR group compared to all other treatments. Almost 100 days post-treatment, 50% survival was observed in the AuNP+IR group compared to 20% in the IR-only groups (p < 0.05).
Conclusions Noninvasive imaging showed that AuNP+IR results in a transient increase and subsequent decline in mean tumor hypoxia, leading to substantial tumor regression and an overall increase in tumor survival. High radiation-induced vascular damage may lead to better tumor reduction and prolonged survival in the human non-small cell lung cancer model.
Citation Format: Olivia J. Kelada, Sijumon Kunjachan, Needa A. Virani, Alexandre Detappe, Jennifer Hayashi, Thomas Ireland, Douglas E. Biancur, Rajiv Kumar, Srinivas Sridhar, Mike Makrigiorgos, Ross I. Berbeco. Noninvasive imaging of tumor hypoxia during radiation-induced tumor vascular disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 85.@misc{baldwin2019combination,
title = {Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib},
author = {Paige Baldwin and Adrienne Orriols and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. As such, Talazoparib (TLZ), a potent PARP inhibitor, offers a way to target the biology of a number of cancers with DNA repair defects until these tumors develop resistance. PARP inhibitors must be used in combination with other inhibitors or chemotherapeutics to reverse resistance and sensitize non-responsive tumors. Dinaciclib, a potent cyclin dependent kinase (CDK) inhibitor, has been shown to sensitize both BRCA wild-type tumors and PARP inhibitor resistant tumors to PARP inhibition through disruption of homologous recombination. In clinical trials, Talazoparib and Dinaciclib have both demonstrated hematologic toxicities, suggesting a combination of these drugs would result in compounded toxicity, leading to dose reduction and an ineffective combination. Nanoparticle delivery systems offer a means to modify the toxicity profiles of these drugs and enhance the therapeutic window, therefore allowing for effective combination treatment.
Methods: Separate nanoformulations of Talazoparib (NanoTLZ) and Dinaciclib (NanoDCB) were optimized, and pharmacokinetics and pharmacodynamics assessed. Nanoformulations were tested alone and in combination in vitro to ensure NanoDCB could sensitize a model with no known DNA repair defects to NanoTLZ. The combination of the two nanoformulations was then assessed for efficacy and toxicity in orthotopic MDA-MB-231 xenografts.
Results: Robust formulations of NanoTLZ and NanoDCB were developed. Each nanoformulation extended the half-life of the drug it encapsulates. A constant low dose of Dinaciclib sensitized MDA-MB-231 cells to Talazoparib, significantly lowering the IC50 value. As a single agent NanoDCB was more effective in vitro than free Dinaciclib. In vivo, the combination of the two nanoformulations was more effective than either single nanoformulation or the combination of the two free drugs. Assessments of hematologic toxicities are underway, but thus far, there were no signs of gross toxicity in the combination therapy group.
Conclusions: The combination of NanoDCB and NanoTLZ has provided an effective method for sensitizing tumors to PARP inhibition that are otherwise nonresponsive to this therapy. The development of two separate nanoformulations has allowed for tailored dosing. These long-circulating nanoformulations have proven more effective than the free drugs in stabilizing tumor growth and were well tolerated. This work was supported by ARMY/W81XWH-16-1-0731.
Citation Format: Paige Baldwin, Adrienne Orriols, Srinivas Sridhar. Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3642.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Separate nanoformulations of Talazoparib (NanoTLZ) and Dinaciclib (NanoDCB) were optimized, and pharmacokinetics and pharmacodynamics assessed. Nanoformulations were tested alone and in combination in vitro to ensure NanoDCB could sensitize a model with no known DNA repair defects to NanoTLZ. The combination of the two nanoformulations was then assessed for efficacy and toxicity in orthotopic MDA-MB-231 xenografts.
Results: Robust formulations of NanoTLZ and NanoDCB were developed. Each nanoformulation extended the half-life of the drug it encapsulates. A constant low dose of Dinaciclib sensitized MDA-MB-231 cells to Talazoparib, significantly lowering the IC50 value. As a single agent NanoDCB was more effective in vitro than free Dinaciclib. In vivo, the combination of the two nanoformulations was more effective than either single nanoformulation or the combination of the two free drugs. Assessments of hematologic toxicities are underway, but thus far, there were no signs of gross toxicity in the combination therapy group.
Conclusions: The combination of NanoDCB and NanoTLZ has provided an effective method for sensitizing tumors to PARP inhibition that are otherwise nonresponsive to this therapy. The development of two separate nanoformulations has allowed for tailored dosing. These long-circulating nanoformulations have proven more effective than the free drugs in stabilizing tumor growth and were well tolerated. This work was supported by ARMY/W81XWH-16-1-0731.
Citation Format: Paige Baldwin, Adrienne Orriols, Srinivas Sridhar. Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3642.@misc{singh2019development,
title = {Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer},
author = {Bijay Singh and Mostafa Abdelhalim and Stephanee Warrington and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
publisher = {American Association for Cancer Research},
abstract = {Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy exploits a synthetic lethality strategy in cancers with inherent damage in DNA repair or transcription pathways. Talazoparib is a potent PARPi that is currently indicated for oral inhibitor therapy in several cancer clinical trials. Oral administration of these inhibitors typically results in poor bioavailability and tumor accumulation. In contrast, nanoparticle formulation provides a safe vehicle for parenteral administration of therapeutic drugs with sustainable release reducing systemic toxicity and also protect from surveillance of immune cells, thereby increasing the bioavailability of the drugs in vivo. Moreover, targeting strategy for the nanoparticles will improve the accumulation of drugs in the tumors. Here, we developed a targeted formulation of Talazoparib (NanoTLZ) which was decorated with anti-EGFR antibody as a ligand to ameliorate the cellular uptake of NanoTLZ via EGFR-mediated endocytosis. In vitro tests showed that NanoTLZ is more effective in cell growth inhibition than free Talazoparib. When combined with radiation with different doses from 2-10Gy, NanoTLZ showed a strong radiosensitization effect as evidenced with almost no colonies formation at 6 Gy of radiation dose. The high therapeutic efficacy of combined chemoradiation therapy in Calu 6 cell line can be attributed to the higher accumulation of NanoTLZ in the cancer cells as compared to the free Talazoparib which is also marred with efflux of the drug from the cells. The slow and sustained release of Talazoparib from nanoparticle formulation inside the cells lead enhanced inhibition of DNA repair pathways. These studies provide very encouraging results to evaluate the efficacy of these nanoparticles in lung cancer animal models.
Citation Format: Bijay Singh, Mostafa Abdelhalim, Stephanee Warrington, Srinivas Sridhar. Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3631.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: Bijay Singh, Mostafa Abdelhalim, Stephanee Warrington, Srinivas Sridhar. Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3631.@article{sridhar2019portable,
title = {Portable VEP Diagnostics for NeuroVisual Disorders},
author = {Srinivas Sridhar and Craig Versek and Ali Banijamali and Anthony Tran and Armando Cardozo and Kameran Lashkari and Peter Bex},
year = {2019},
date = {2019-01-01},
urldate = {2019-01-01},
journal = {Investigative Ophthalmology & Visual Science},
volume = {60},
number = {9},
pages = {3591--3591},
publisher = {The Association for Research in Vision and Ophthalmology},
abstract = {Purpose: Visual Evoked Potentials (VEPs) provide objective neuro-opthalmologic assessments that avoid patient task performance but utilizes invasive and cumbersome apparatus. We have developed a system that combines a scalp neuroelectric potential and field sensor with a smartphone in a portable wireless display headset called the NeuroDotVR (Figure 1). The system records VEPs and Fields (VEPF) in response to dichoptic stimuli presented on the smartphone display for a range of neuro-oplthalmologic disorders. We evaluate the NeuroDotVR for Dark Adaptation Recovers (DAR), a key biomarker for age-related macular degeneration (AMD).
Methods: DAR was measured simultaneously in both eyes of# patients with AMD and# age-matched controls. Following a 60s photobleach (400 cd/m 2 white cellphone screen), recovery of visual sensitivity was recorded with VEPFs to pattern reversal checkerboard …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methods: DAR was measured simultaneously in both eyes of# patients with AMD and# age-matched controls. Following a 60s photobleach (400 cd/m 2 white cellphone screen), recovery of visual sensitivity was recorded with VEPFs to pattern reversal checkerboard …@article{di2019nano,
title = {A nano-liposome formulation of the PARP inhibitor Talazoparib enhances treatment efficacy and modulates immune cell populations in mammary tumors of BRCA-deficient mice},
author = {Paige Baldwin Di Zhang and Ana S Leal and Sarah Carapellucci and Srinivas Sridhar and Karen T Liby},
year = {2019},
date = {2019-01-01},
journal = {Theranostics},
volume = {9},
number = {21},
pages = {6224},
publisher = {Ivyspring International Publisher},
abstract = {Two recently approved PARP inhibitors provide an important new therapeutic option for patients with BRCA-mutated metastatic breast cancer. PARP inhibitors significantly prolong progression-free survival in patients, but conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and off-target toxicities, thus compromising the therapeutic benefits and quality of life for patients. Here, we developed a new delivery system, in which the PARP inhibitor Talazoparib is encapsulated in the bilayer of a nano-liposome, to overcome these limitations.
Methods: Nano-Talazoparib (NanoTLZ) was characterized both in vitro and in vivo. The therapeutic efficacy and toxicity of Nano-Talazoparib (NanoTLZ) were evaluated in BRCA-deficient mice. The regulation of NanoTLZ on gene transcription and immunomodulation were further investigated in spontaneous BRCA-deficient tumors.
Results: NanoTLZ significantly (p<0.05) prolonged the overall survival of BRCA-deficient mice compared to all of the other experimental groups, including saline control, empty nanoparticles, and free Talazoparib groups (oral and i.v.). Moreover, NanoTLZ was better tolerated than treatment with free Talazoparib, with no significant weight lost or alopecia as was observed with the free drug. After 5 doses, NanoTLZ altered the expression of over 140 genes and induced DNA damage, cell cycle arrest and inhibition of cell proliferation in the tumor. In addition, NanoTLZ favorably modulated immune cell populations in vivo and significantly (p<0.05) decreased the percentage of myeloid derived suppressor cells in both the tumor and spleen compared to control groups.
Conclusions: Our results demonstrate that delivering nanoformulated Talazoparib not only enhances treatment efficacy but also reduces off-target toxicities in BRCA-deficient mice; the same potential is predicted for patients with BRCA-deficient breast cancer.
Keywords: PARP inhibitor, Talazoparib, Nanoparticle, BRCA-deficient breast cancer, immunomodulation},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methods: Nano-Talazoparib (NanoTLZ) was characterized both in vitro and in vivo. The therapeutic efficacy and toxicity of Nano-Talazoparib (NanoTLZ) were evaluated in BRCA-deficient mice. The regulation of NanoTLZ on gene transcription and immunomodulation were further investigated in spontaneous BRCA-deficient tumors.
Results: NanoTLZ significantly (p<0.05) prolonged the overall survival of BRCA-deficient mice compared to all of the other experimental groups, including saline control, empty nanoparticles, and free Talazoparib groups (oral and i.v.). Moreover, NanoTLZ was better tolerated than treatment with free Talazoparib, with no significant weight lost or alopecia as was observed with the free drug. After 5 doses, NanoTLZ altered the expression of over 140 genes and induced DNA damage, cell cycle arrest and inhibition of cell proliferation in the tumor. In addition, NanoTLZ favorably modulated immune cell populations in vivo and significantly (p<0.05) decreased the percentage of myeloid derived suppressor cells in both the tumor and spleen compared to control groups.
Conclusions: Our results demonstrate that delivering nanoformulated Talazoparib not only enhances treatment efficacy but also reduces off-target toxicities in BRCA-deficient mice; the same potential is predicted for patients with BRCA-deficient breast cancer.
Keywords: PARP inhibitor, Talazoparib, Nanoparticle, BRCA-deficient breast cancer, immunomodulation@article{qiao2019data,
title = {Data on MRI brain lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization},
author = {Ju Qiao and Xuezhu Cai and Qian Xiao and Zhengxi Chen and Praveen Kulkarni and Craig Ferris and Sagar Kamarthi and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
journal = {Data in brief},
volume = {27},
pages = {104628},
publisher = {Elsevier},
abstract = {The data in this article provide details about MRI lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization (GMM-EM) algorithms. Both K-means and GMM-EM algorithms can segment lesion area from the rest of brain MRI automatically. The performance metrics (accuracy, sensitivity, specificity, false positive rate, misclassification rate) were estimated for the algorithms and there was no significant difference between K-means and GMM-EM. In addition, lesion size does not affect the accuracy and sensitivity for either method.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{bal2019vivo,
title = {In Vivo Endothelial Uptake of Nanoparticles: Impact of Disturbed Flow and Degraded Glycocalyx},
author = {Nandita Bal and Ming Cheng and Rajiv Kumar and Srinivas Sridhar and Eno E Ebong},
year = {2019},
date = {2019-01-01},
booktitle = {2019 AIChE Annual Meeting},
organization = {AIChE},
abstract = {Statement of Purpose: New and more effective therapies for atherosclerosis-based cardiovascular disease should target early stages of the diseases and specific vascular sites where disease occurs.1 The initiation and localization of atherosclerotic plaques has been linked to the dysfunction of the endothelial glycocalyx (GCX). The GCX breaks down, resulting in compromised endothelial barrier function and an increase in vascular permeability.2 This allows lipids and inflammatory cells to penetrate vessel walls, and at the same time can be leveraged for targeted therapeutic delivery. In previous cell culture studies, enzyme-induced GCX degradation resulted in significantly increased endothelial cell uptake of nanoparticle vehicles that are designed for drug delivery, compared to the effects of intact GCX.3,4 The study presented in this abstract was designed to assess if the cell culture findings translate to selective nanoparticle uptake in animals. Specifically, it was determined if increased nanoparticle uptake occurs in animal endothelial cells that have degraded GCX. The first objective of this animal study was to identify vessel regions with intact versus degraded GCX, and confirm that circulating nanoparticles localize selectively at regions of GCX dysfunction. The second objective was to promote endothelial cell surface-specific localization of these nanoparticles by targeting the intracellular adhesion molecule (ICAM) which is upregulated in pre-atherosclerotic disturbed flow conditions.5
Methods: Mouse models of endothelial dysfunction apply partial ligation of the left carotid artery (LCA) to model acute disturbed flow in the mice, which has been reported to induce endothelial dysfunction.6,7 Seven C57BL/6 mice at 4 weeks of age underwent this partial LCA ligation surgery. Polymer- and biotin-coated 10 nm gold nanospheres (GNS) were administered to the mice at day 26 after LCA ligation. In the case of targeted delivery to the endothelial cell surface, an anti-ICAM peptide was conjugated to the GNS surface before it was administered to the mice. The animals were euthanized 2 days after receiving the GNS without or conjugated with anti-ICAM. The LCA and right carotid artery (RCA) were separately cryopreserved and sectioned onto slides. GCX was imaged after incubating LCA and RCA sections with antibody to block GNS, followed by biotinylated wheat germ agglutinin and horseradish peroxidase conjugated to streptavidin. GNS were imaged after incubation with horseradish peroxidase conjugated to streptavidin. We then applied a fluorescent reagent that reacts with horseradish peroxidase. The blood vessels were imaged by fluorescence microscopy and analyzed using ImageJ for GCX coverage and GNS uptake.
Results: The partial LCA ligation model achieved the goal of creating a vessel with disturbed flow. The model also provided a convenient comparison with a healthy RCA experiencing streamlined flow. The vessel walls of the LCA exhibited a more discontinuous GCX layer on the intima as compared to the RCA, decreasing from 76.3 ± 10.2 % in the RCA to 21.2 ± 5.9 % in the LCA. This observable dysfunction correlated to increased nanoparticle uptake, as the LCA took in approximately 2.5-fold more GNS than the RCA did, based on the fluorescence signal detected in the histology images. The studies to improve endothelial cell surface-specific localization of these nanoparticles by targeting ICAM are still ongoing.
Conclusions: A partial LCA ligation was performed to acutely disturb blood flow in a mouse vessel and observe resultant endothelial GCX dysfunction as well as passive targeting of GNS to affected areas. The affected LCA exhibited lack of continuous GCX layer, as well as increased localization of plolymer-coated GNS that are designed to deliver drug therapies. These results indicate that vessel and GCX dysfunction, both precursors of atherosclerosis and cardiovascular disease, can be induced in a mouse model to study targeted drug delivery. Passive nanoparticle uptake differences between the healthy RCA and disturbed LCA indicate a role of GCX infiltration of nanoparticles to the endothelial cells. The ongoing investigation will determine the effectiveness of active targeting with ICAM to localize these nanoparticles to the endothelial cell surface. This strategy of targeting dysfunctional vessels based on the GCX offers a new approach in cardiovascular disease therapy and prevention.
Acknowledgements: We appreciate funding from National Institutes of Health (K01 HL125499) and the Northeastern University Provost’s Tier 1 Grant.
References:
Weinbaum, S.; et. al, Annu Rev Biomed Eng 2007, 9,121-167.
Becker, B. et. al, Br J Clin Pharmacol 2015, 80, 389-402.
Cheng, et. al, Int. J. Nanomed 2016, 21, 3305-3315.
Cheng, et. al, Int. J. Nanomed 2019, 14, 319-333.
Nakashima et. al, Arteriosclerosis, Thrombosis, and Vascular Biology 1998, 18, 842-851.
Kumar, S.; et. al, J. Lab. Invest. 2017, 97, 935-945
Mitra, et. al, Trans. Med. Comm. 2018, 3-10.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Methods: Mouse models of endothelial dysfunction apply partial ligation of the left carotid artery (LCA) to model acute disturbed flow in the mice, which has been reported to induce endothelial dysfunction.6,7 Seven C57BL/6 mice at 4 weeks of age underwent this partial LCA ligation surgery. Polymer- and biotin-coated 10 nm gold nanospheres (GNS) were administered to the mice at day 26 after LCA ligation. In the case of targeted delivery to the endothelial cell surface, an anti-ICAM peptide was conjugated to the GNS surface before it was administered to the mice. The animals were euthanized 2 days after receiving the GNS without or conjugated with anti-ICAM. The LCA and right carotid artery (RCA) were separately cryopreserved and sectioned onto slides. GCX was imaged after incubating LCA and RCA sections with antibody to block GNS, followed by biotinylated wheat germ agglutinin and horseradish peroxidase conjugated to streptavidin. GNS were imaged after incubation with horseradish peroxidase conjugated to streptavidin. We then applied a fluorescent reagent that reacts with horseradish peroxidase. The blood vessels were imaged by fluorescence microscopy and analyzed using ImageJ for GCX coverage and GNS uptake.
Results: The partial LCA ligation model achieved the goal of creating a vessel with disturbed flow. The model also provided a convenient comparison with a healthy RCA experiencing streamlined flow. The vessel walls of the LCA exhibited a more discontinuous GCX layer on the intima as compared to the RCA, decreasing from 76.3 ± 10.2 % in the RCA to 21.2 ± 5.9 % in the LCA. This observable dysfunction correlated to increased nanoparticle uptake, as the LCA took in approximately 2.5-fold more GNS than the RCA did, based on the fluorescence signal detected in the histology images. The studies to improve endothelial cell surface-specific localization of these nanoparticles by targeting ICAM are still ongoing.
Conclusions: A partial LCA ligation was performed to acutely disturb blood flow in a mouse vessel and observe resultant endothelial GCX dysfunction as well as passive targeting of GNS to affected areas. The affected LCA exhibited lack of continuous GCX layer, as well as increased localization of plolymer-coated GNS that are designed to deliver drug therapies. These results indicate that vessel and GCX dysfunction, both precursors of atherosclerosis and cardiovascular disease, can be induced in a mouse model to study targeted drug delivery. Passive nanoparticle uptake differences between the healthy RCA and disturbed LCA indicate a role of GCX infiltration of nanoparticles to the endothelial cells. The ongoing investigation will determine the effectiveness of active targeting with ICAM to localize these nanoparticles to the endothelial cell surface. This strategy of targeting dysfunctional vessels based on the GCX offers a new approach in cardiovascular disease therapy and prevention.
Acknowledgements: We appreciate funding from National Institutes of Health (K01 HL125499) and the Northeastern University Provost’s Tier 1 Grant.
References:
Weinbaum, S.; et. al, Annu Rev Biomed Eng 2007, 9,121-167.
Becker, B. et. al, Br J Clin Pharmacol 2015, 80, 389-402.
Cheng, et. al, Int. J. Nanomed 2016, 21, 3305-3315.
Cheng, et. al, Int. J. Nanomed 2019, 14, 319-333.
Nakashima et. al, Arteriosclerosis, Thrombosis, and Vascular Biology 1998, 18, 842-851.
Kumar, S.; et. al, J. Lab. Invest. 2017, 97, 935-945
Mitra, et. al, Trans. Med. Comm. 2018, 3-10.@article{kunjachan2019selective,
title = {Selective priming of tumor Blood Vessels by Radiation therapy enhances nanodrug Delivery},
author = {Sijumon Kunjachan and Shady Kotb and Robert Pola and Michal Pechar and Rajiv Kumar and Bijay Singh and Felix Gremse and Reza Taleeli and Florian Trichard and Vincent Motto-Ros and others},
year = {2019},
date = {2019-01-01},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {1--14},
publisher = {Nature Publishing Group},
abstract = {Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{baldwin2019abstract,
title = {Abstract NT-087: NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL},
author = {Paige Baldwin and Anders Ohman and Jamie Medina and Daniela Dinulescu and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
publisher = {American Association for Cancer Research},
abstract = {Talazoparib, a potent PARP inhibitor (PARPi), induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARPi's. We sought to formulate Talazoparib in a nanoparticle delivery system such that the drug could be administered intraperitoneally, localizing the entire dose at the disease site, to increase therapeutic efficacy and minimize toxicity. NanoTalazoparib was formulated and characterized and found to have a mean diameter of 70 nm and a neutral surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine tubal and human HGSOC cell lines and dose response compared to the first clinically approved PARPi, Olaparib. Dose response data indicated all cell lines were more sensitive to Talazoparib and NanoTalazoparib than Olaparib and all lines showed the same sensitivity to nanoformulations as free drugs. The human cell lines had various BRCA mutations and deletions, as well as a homologous recombination proficient (HRP) line, however, the HRP line was more sensitive to treatment than some HRD lines. Therapeutic efficacy was tested in vivo in a murine cancer model that mimics disseminated peritoneal disease. NanoTalazoparib 3X weekly for 8 weeks did not shrink tumors but resulted in tumor growth inhibition of 64% while an equivalent dose of oral Talazoparib only resulted in 34% growth inhibition. NanoTalazoparib suppressed the average volume of ascites at the study endpoint by 3.45 times more than oral Talazoparib. H&E staining of the tissues indicated no significant toxicity to the organs of the mononuclear phagocyte system. These results indicate that NanoTalazoparib can be used to localize PARPi therapy to the peritoneal cavity for disseminated late stage ovarian cancer treatment. Our data suggests that NanoTalazoparib could be utilized to delay the formation of tumor ascites for women with HR-deficient disease. While NanoTalazoparib did not effectively treat the disseminated disease at this dose, it may have clinical utility, either in combination with other therapies or as a maintenance therapy. Preclinical data indicates PARP inhibitors potentiate damage when combined with other cytotoxic treatments, however, in the clinic this has resulted in enhanced toxicity, forcing dose reduction and delay. The IP administration of NanoTalazoparib may provide a route to bypass some of the toxicities that have plagued combination treatments.
Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program
Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program
Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.@article{baldwin2019nanoformulationb,
title = {Nanoformulation of talazoparib increases maximum tolerated doses in combination with temozolomide for treatment of Ewing sarcoma},
author = {Paige Baldwin and Rostislav Likhotvorik and Nabeela Baig and Jodie Cropper and Ruth Carlson and Raushan Kurmasheva and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
journal = {Frontiers in Oncology},
volume = {9},
pages = {1416},
publisher = {Frontiers},
abstract = {The Pediatric Preclinical Testing Program previously identified the PARP inhibitor talazoparib (TLZ) as a means to potentiate temozolomide (TMZ) activity for the treatment of Ewing sarcoma. However, the combination of TLZ and TMZ has been toxic in both preclinical and clinical testing, necessitating TMZ dose reduction to ~15% of the single agent maximum tolerated dose. We have synthesized a nanoparticle formulation of talazoparib (NanoTLZ) to be administered intravenously in an effort to modulate the toxicity profile of this combination treatment. Results in Ewing sarcoma xenograft models are presented to demonstrate the utility of this delivery method both alone and in combination with TMZ. NanoTLZ reduced gross toxicity and had a higher maximum tolerated dose than oral TLZ. The dose of TMZ did not have to be reduced when combined with NanoTLZ as was required when combined with oral TLZ. This indicated the NanoTLZ delivery system may be advantageous in decreasing the systemic toxicity associated with the combination of oral TLZ and TMZ.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{singh2019abstract,
title = {Abstract A104: Nanoformulations of PARP and CDK inhibitors for cancer therapy},
author = {Bijay Singh and Shicheng Yang and Paige Baldwin and Anne van de Ven and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
publisher = {American Association for Cancer Research},
abstract = {Poly(ADP-ribose) polymerase (PARP) inhibitors have been majorly utilized in cancers with BRCA1/2 mutations that have deficiencies in the homologous recombination (HR) DNA repair pathway. Traditionally, PARP inhibitors have been administered through oral route in the clinic but they have resulted in poor bioavailability, low tumor accumulation and high systemic toxicity. Moreover, tumors develop resistance to PARP inhibitors necessitating the development of strategies to re-sensitize these resistant tumors. To overcome these limitations, nanoparticle drug formulation has demonstrated a great potential to increase the drug concentration and accumulation at tumor sites with low systemic toxicities. Here we report the development of several nanoformulations of PARP inhibitors and observe their efficacies by systemic administration to treat various cancer diseases. We used two FDA approved PARP inhibitors (Olaparib or Talazoparib) for nanoformulations of NanoOlaparib and NanoTalazoparib, decorated with EpCAM or EGFR antibody, and tested on breast, ovarian, prostate and lung cancer with or without irradiation. In HR deficient models, the nanoformulations showed significant inhibition of tumor cell growth in vitro and in vivo. Above all, combination of PARP inhibitor with irradiation resulted in greater efficacy in lung and prostate cancer models. To overcome PARP inhibitor resistance, we formulated nanoparticles, NanoDinaciclib of cyclin-dependent kinase 12 (CDK12) inhibitor (dinaciclib) and used in combination with nanoformulation of PARP inhibitor to arrest the tumor growth in animal model. Our current research reveals that the use of CDK12 inhibitor in PARP resistant tumors further arrests tumor growth compared with monotherapy alone. Further studies will help clarify to achieve clear understanding of the mechanism of action CDK12 inhibitor to determine the best way to use PARP inhibitors beyond HR deficiency.
Citation Format: Bijay Singh, Shicheng Yang, Paige Baldwin, Anne van de Ven, Srinivas Sridhar. Nanoformulations of PARP and CDK inhibitors for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A104. doi:10.1158/1535-7163.TARG-19-A104
©2019 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: Bijay Singh, Shicheng Yang, Paige Baldwin, Anne van de Ven, Srinivas Sridhar. Nanoformulations of PARP and CDK inhibitors for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A104. doi:10.1158/1535-7163.TARG-19-A104
©2019 American Association for Cancer Research.@inproceedings{baldwin2019nanoformulationc,
title = {NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL},
author = {Paige Baldwin and Anders Ohman and Jamie Medina and Daniela Dinulescu and Srinivas Sridhar},
year = {2019},
date = {2019-01-01},
booktitle = {CLINICAL CANCER RESEARCH},
volume = {25},
number = {22},
pages = {198--198},
organization = {AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~…},
abstract = {Talazoparib, a potent PARP inhibitor (PARPi), induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARPi's. We sought to formulate Talazoparib in a nanoparticle delivery system such that the drug could be administered intraperitoneally, localizing the entire dose at the disease site, to increase therapeutic efficacy and minimize toxicity. NanoTalazoparib was formulated and characterized and found to have a mean diameter of 70 nm and a neutral surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine tubal and human HGSOC cell lines and dose response compared to the first clinically approved PARPi, Olaparib. Dose response data indicated all cell lines were more sensitive to Talazoparib and NanoTalazoparib than Olaparib and all lines showed the same sensitivity to nanoformulations as free drugs. The human cell lines had various BRCA mutations and deletions, as well as a homologous recombination proficient (HRP) line, however, the HRP line was more sensitive to treatment than some HRD lines. Therapeutic efficacy was tested in vivo in a murine cancer model that mimics disseminated peritoneal disease. NanoTalazoparib 3X weekly for 8 weeks did not shrink tumors but resulted in tumor growth inhibition of 64% while an equivalent dose of oral Talazoparib only resulted in 34% growth inhibition. NanoTalazoparib suppressed the average volume of ascites at the study endpoint by 3.45 times more than oral Talazoparib. H&E staining of the tissues indicated no significant toxicity to the organs of the mononuclear phagocyte system. These results indicate that NanoTalazoparib can be used to localize PARPi therapy to the peritoneal cavity for disseminated late stage ovarian cancer treatment. Our data suggests that NanoTalazoparib could be utilized to delay the formation of tumor ascites for women with HR-deficient disease. While NanoTalazoparib did not effectively treat the disseminated disease at this dose, it may have clinical utility, either in combination with other therapies or as a maintenance therapy. Preclinical data indicates PARP inhibitors potentiate damage when combined with other cytotoxic treatments, however, in the clinic this has resulted in enhanced toxicity, forcing dose reduction and delay. The IP administration of NanoTalazoparib may provide a route to bypass some of the toxicities that have plagued combination treatments.
Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program
Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.
©2019 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program
Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.
©2019 American Association for Cancer Research.@article{cheng2018synthesis,
title = {Synthesis of functionalized 10-nm polymer-coated gold particles for endothelium targeting and drug delivery},
author = {Ming J Cheng and Priya Prabakaran and Rajiv Kumar and Srinivas Sridhar and Eno E Ebong},
year = {2018},
date = {2018-01-01},
journal = {JoVE (Journal of Visualized Experiments)},
number = {131},
pages = {e56760},
abstract = {Gold nanoparticles (AuNPs) have been used extensively in medical research due to their size, biocompatibility, and modifiable surface. Specific targeting and drug delivery are some of the applications of these AuNPs, but endothelial extracellular matrices' defensive properties hamper particle uptake. To address this issue, we describe a synthesis method for ultrasmall gold nanoparticles to improve vascular delivery, with customizable functional groups and polymer lengths for further adjustments. The protocol yields 2.5 nm AuNPs that are capped with tetrakis(hydroxymethyl)phosphonium chloride (THPC). The replacement of THPC with hetero-functional polyethylene glycol (PEG) on the surface of the AuNP increases the hydrodynamic radius to 10.5 nm while providing various functional groups on the surface. The last part of the protocol includes an optional addition of a fluorophore to allow the AuNPs to be visualized under fluorescence to track nanoparticle uptake. Dialysis and lyophilization were used to purify and isolate the AuNPs. These fluorescent nanoparticles can be visualized in both in vitro and in vivo experiments due to the biocompatible PEG coating and fluorescent probes. Additionally, the size range of these nanoparticles render them an ideal candidate for probing the glycocalyx without disrupting normal vasculature function, which may lead to improved delivery and therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gharagouzloo2018dataset,
title = {Dataset on a 173 region awake resting state quantitative cerebral blood volume rat brain atlas and regional changes to cerebral blood volume under isoflurane anesthetization and CO2 challenge},
author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
journal = {Data in brief},
volume = {17},
pages = {393--396},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{kunjachan2018targeted,
title = {Targeted Drug Delivery by Radiation-Induced Tumor Vascular Modulation},
author = {Sijumon Kunjachan and Shady Kotb and Rajiv Kumar and Robert Pola and Michal Pechar and Felix Gremse and Reza Taleeli and Florian Trichard and Vincent Motto-Ros and Lucie Sancey and others},
year = {2018},
date = {2018-01-01},
journal = {bioRxiv},
pages = {268714},
publisher = {Cold Spring Harbor Laboratory},
abstract = {Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a short-circulating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a long-circulating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h). Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gupta2018synthesis,
title = {Synthesis and in vitro studies of PLGA-DTX nanoconjugate as potential drug delivery vehicle for oral cancer},
author = {Parul Gupta and Manjri Singh and Rajiv Kumar and Jodi Belz and Rishi Shanker and Premendra D Dwivedi and Srinivas Sridhar and Surinder P Singh},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
number = {T-NANO 2014 Abstracts},
pages = {67},
publisher = {Dove Press},
abstract = {Advances in nanotechnology have led to the design of multifunctional nanoparticles capable of cellular imaging, targeted drug delivery, and diagnostics for early cancer detection. We synthesized poly(lactic-co-glycolic acid) nanoparticles encapsulating a model radiosensitizing drug docetaxel accomplishing localized in situ delivery of the sensitizer to the tumor site. The synthesized nanoparticles have been characterized for their physicochemical properties. The in vitro cytotoxicity of drug-loaded nanoparticles has been studied on human tongue carcinoma cell line SCC-9 (ATCC-CRL-1629).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{baronia2018synthesis,
title = {Synthesis and characterization of multifunctional gold nanoclusters for application in radiation therapy},
author = {Richa Baronia and Manjri Singh and Rajat B Gupta and Stalin Karuppiah and Rajiv Kumar and Jodi Belz and Rishi Shanker and Srinivas Sridhar and Surinder P Singh},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
number = {T-NANO 2014 Abstracts},
pages = {113},
publisher = {Dove Press},
abstract = {Gold nanoparticles, because of their high radiation absorption coefficient and efficient generation of secondary photoelectrons, have been predicted to enhance therapeutic efficacy in radiation therapy. However, high dose for effective treatment limits their use. We have synthesized multifunctional gold nanoclusters (GNCs) that can be used for imaging and radiation therapy. The designed GNCs have been characterized for their physicochemical properties, biocompatibility, and their radiation dose enhancement potential on PC3 cell lines.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{baldwin2018vitro,
title = {In vitro analysis of pArp inhibitor nanoformulations},
author = {Paige Baldwin and Shifalika Tangutoori and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
number = {T-NANO 2014 Abstracts},
pages = {59},
publisher = {Dove Press},
abstract = {PARP-l is a DNA repair protein that plays a role in a number of repair pathways and also helps in transcriptional regulation; thus PARP inhibitors (PARPi), such as olaparib and BMN-673, act by inhibiting DNA damage repair. This leads to an accumulation of deleterious mutations leading to genetic instability as a result of a number of cell replications. Currently, olaparib is only available in an oral form and has poor bioavailability, consequently leading to poor accumulation in the tumor due to first-pass metabolism. Therefore, in the present study, an injectable nanoparticle formulation of olaparib was created that offers a delivery route in which the drug would be fully bioavailable in the vasculature, suggesting greater tumor accumulation. Our results illustrated that injectable nanoformulations of olaparib and BMN-673, a next generation PARPi, could be developed, and an efficacy test indicated that BMN-673 is a much more potent PARPi than olaparib. The success of these molecular inhibitors as a monotherapy in inhibiting colony formation suggests enhanced efficacy of these treatments in combination with other therapies, even in tumors which have developed resistance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{upponi2018polymeric,
title = {Polymeric micelles: Theranostic co-delivery system for poorly water-soluble drugs and contrast agents},
author = {Jaydev R Upponi and Kaushal Jerajani and Dattatri K Nagesha and Praveen Kulkarni and Srinivas Sridhar and Craig Ferris and Vladimir P Torchilin},
year = {2018},
date = {2018-01-01},
journal = {Biomaterials},
volume = {170},
pages = {26--36},
publisher = {Elsevier},
abstract = {Interest in theranostic agents has continued to grow because of their promise for simultaneous cancer detection and therapy. A platform-based nanosized combination agent suitable for the enhanced diagnosis and treatment of cancer was prepared using polymeric polyethylene glycol-phosphatidylethanolamine-based micelles loaded with both, poorly soluble chemotherapeutic agent paclitaxel and hydrophobic superparamagnetic iron oxide nanoparticles (SPION), a Magnetic Resonance Imaging contrast agent. The co-loaded paclitaxel and SPION did not affect each other's functional properties in vitro. In vivo, the resulting paclitaxel-SPION-co-loaded PEG-PE micelles retained their Magnetic Resonance contrast properties and apoptotic activity in breast and melanoma tumor mouse models. Such theranostic systems are likely to play a significant role in the combined diagnosis and therapy that leads to a more personalized and effective form of treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{versek2018electric,
title = {Electric field encephalography for brain activity monitoring},
author = {C Versek and T Frasca and J Zhou and K Chowdhury and S Sridhar},
year = {2018},
date = {2018-01-01},
journal = {Journal of neural engineering},
volume = {15},
number = {4},
pages = {046027},
publisher = {IOP Publishing},
abstract = {Objective. We describe an early-stage prototype of a new wireless electrophysiological sensor system, called NeuroDot, which can measure neuroelectric potentials and fields at the scalp in a new modality called Electric Field Encephalography (EFEG). We aim to establish the physical validity of the EFEG modality, and examine some of its properties and relative merits compared to EEG. Approach. We designed a wireless neuroelectric measurement device based on the Texas Instrument ADS1299 Analog Front End platform and a sensor montage, using custom electrodes, to simultaneously measure EFEG and spatially averaged EEG over a localized patch of the scalp (2 cm × 2 cm). The signal properties of each modality were compared across tests of noise floor, Berger effect, steady-state visually evoked potential (ssVEP), signal-to-noise ratio (SNR), and others. In order to compare EFEG to EEG modalities in the frequency domain, we use a novel technique to compute spectral power densities and derive narrow-band SNR estimates for ssVEP signals. A simple binary choice brain–computer-interface (BCI) concept based on ssVEP is evaluated. Also, we present examples of high quality recording of transient Visually Evoked Potentials and Fields (tVEPF) that could be used for neurological studies. Main results. We demonstrate the capability of the NeuroDot system to record high quality EEG signals comparable to some recent clinical and research grade systems on the market. We show that the locally-referenced EFEG metric is resistant to certain types of movement artifacts. In some ssVEP based measurements, the EFEG modality shows promising results, demonstrating superior signal to noise ratios than the same recording processed as an analogous EEG signal. We show that by using EFEG based ssVEP SNR estimates to perform a binary classification in a model BCI, the optimal information transfer rate (ITR) can be raised from 15 to 30 bits per minute—though these preliminary results are likely sensitive to inter-subject variations and choice of scalp locations, so require further investigation. Significance. Enhancement of ssVEP SNR using EFEG has the potential to improve visually based BCIs and diagnostic paradigms. The time domain analysis of tVEPF signals shows robust features in the electric field components that might have clinical relevance beyond classical VEP approaches.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@techreport{thanh2018nanoscale,
title = {Nanoscale Magnetism in Next Generation Magnetic Nanoparticles},
author = {Nguyen Thanh and Xuan Phuc and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
institution = {UNIVERSITY COLLEGE LONDON London United Kingdom},
abstract = {Short summary of most important research results that explain why the work was done, what was accomplished, and how it pushed scientific frontiers or advanced the field. This summary will be used for archival purposes and will be added to a searchable DoD database. Magnetic nanoparticles (MNPs) are key components of a variety of sensors for diverse applications in electronics and biotechnologies. Nanoparticle properties are critically affected both by nanoscale size as well as surface interactions with the environment. These interactions among the key fundamental properties such as magnetic moment and dynamic response that are required for use in applications. In this we have had a collaborative project between groups at Northeastern University (USA), University College London-UCL (UK) and Institute of Materials Science (Vietnam Academy of Science and Technology-VAST) to synthesis and understand the fundamental aspects of magnetism at the nanometer length scale in confined geometries in nanoparticles. At Northeastern University, we studied the dynamic relaxation of superparamagnetic iron oxide nanoparticles (SPIONs) in aqueous media. Using the MRI facilities at Northeastern University, MNPs from collaborators UCL and VAST as well as dextran coated SPIONs were studied. From the measured T1 and T2 relaxation times, a new method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) was developed. The method was tested in vivo and demonstrated to yield positive contrast angiograms with high clarity and definition, and enabled quantitative MRI in biological samples. At UCL, the work included (i) fabricating multi-element magnetic systems, and (ii) controlling interactions by surface modification using organic compounds. The project involves systematic matter property studies by fabrication of novel organically modified coating of MNPs, physical characterization at both macroscopic level such as magnetic moments and AC susceptibility as well as microscopic one. The results provided fundamental insights into the nature of nanoscale magnetism relevant to a variety of nanomagnetic applications.At Institute of Materials Science, Vietnam Academy of Science and Technology, apart from the effort to synthesize MNPs of high magnetization and monodispersity, we have also studied in details various parameters which may impact on magnetic heating power of MNPs of different materials, such as particle size, size distribution, ferrofluid viscosity etc. The 3-year collaborative project has resulted in 9 publications in peer-reviewed journals and 34 presentations in major conferences, meeting and workshops around the world.
},
keywords = {},
pubstate = {published},
tppubtype = {techreport}
}
@article{guthier2018determining,
title = {Determining optimal eluter design by modeling physical dose enhancement in brachytherapy},
author = {CV Guthier and AV D'Amico and MT King and PL Nguyen and PF Orio and S Sridhar and GM Makrigiorgos and RA Cormack},
year = {2018},
date = {2018-01-01},
journal = {Medical physics},
volume = {45},
number = {8},
pages = {3916--3925},
abstract = {Purpose
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
Materials and methods
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
Results
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Conclusions
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.
Materials and methods
The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125I permanent prostate implants. Compound concentrations were calculated using steady‐state solution to the diffusion equation including an elimination term characterized by the diffusion‐elimination modulus (ϕb). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion‐elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.
Results
The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3, ϕb from 0.01 to 4 mm−1, csat from 0.05 to 7.5 times the steady‐state compound concentration released from the surface of the eluter. The number of used eluters (ne) was simulated from 10 to 60 eluters. For the region of (c sat , Φ)‐space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c sat , Φ)‐space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.
Conclusions
Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.
@misc{zhang2018developing,
title = {Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer},
author = {Di Zhang and Paige Baldwin and Srinivas Sridhar and Karen Liby},
year = {2018},
date = {2018-01-01},
urldate = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre;p53+/- mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.
Citation Format: Di Zhang, Paige Baldwin, Srinivas Sridhar, Karen Liby. Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3874.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: Di Zhang, Paige Baldwin, Srinivas Sridhar, Karen Liby. Developing a nanoformulation of the PARP inhibitor talazoparib as a novel delivery for treatment of BRCA-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3874.
©2018 American Association for Cancer Research.@misc{vazquez2018nanoparticle,
title = {Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer},
author = {Ana G Vazquez-Pagan and Paige Baldwin and Ravina M Ashtaputre and Sijumon Kunjachan and Srinivas Sridhar and Rajiv Kumar and Ross Berbeco},
year = {2018},
date = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: More than 50% of cancer patients receive radiation therapy at some point during their care. Gold nanoparticles (GNPs) can amplify the radiation dose by facilitating the ejection of low-energy photoelectrons, resulting in increased DNA damage. One of the main challenges of radiation therapy in cancer is to sustain this damage for longer durations. DNA single-strand breaks (SSBs) are repaired by base excision repair, which utilizes Poly(ADP-ribose) polymerase (PARP). PARP inhibition during radiotherapy provides an attractive alternative in maximizing treatment outcomes. Here, we explore a strategy to combine the radiosensitizing effect of GNPs with the DNA-repair inhibiting ability of NanoTalazoparib (nTLZ), a liposomal formulation of the PARP inhibitor, talazoparib (TLZ).
Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments.
Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way.
Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer.
This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: GNPs were synthesized by reducing AuCl4 using Tetrakis(hydroxymethyl)phosphonium chloride and further PEGylating using heterobifunctional PEGs. A liposomal formulation of TLZ was synthesized using the Nanoassemblr, a microfluidics-based device. Physicochemical characterization of GNPs and nTLZ was carried out using TEM, DLS and release kinetics studies. In vitro studies were carried out to assess the toxicity of the GNPs using MTT assay in non-small cell lung cancer (NSCLC) cell line Calu-6. The therapeutic efficacy of combination treatment using GNPs, nTLZ and radiation was done using clonogenic survival assays. Clonogenic assay was carried out using Calu 6 cells, which were sequentially treated with GNPs (1mg/mL), TLZ (0.5 uM) and nTLZ (0.5 uM) with and without radiation. The radiation doses varied from 0-10Gy for each set of treatments.
Results: PEGylated GNP's showed a hydrodynamic diameter of ~10-12 nm with a spherical morphology whereas nTLZ size was 70 nm encapsulating TLZ at a concentration of ~200 ug/ml. MTT assay showed no toxicity for PEGylated GNPs treated upto a concentration of 3.0 mg/mL. Cells treated with either GNPs, TLZ or nTLZ did not show significant reduction in colony formation, but were reduced with increasing doses of radiation. The survival plots showed a highly additive antiproliferative effect for the GNP + nTLZ combination at all radiation doses, while the free TLZ + GNPs combination was not as effective at inhibiting colony formation. In vivo experiments assessing the combination therapy in a subcutaneous xenograft mice model using Calu 6 are currently under way.
Conclusions: The preliminary in vitro results indicate that the combination of radiosensitizing GNPs with a potent DNA repair enzyme inhibitor, TLZ, has an immense potential as a complimentary combination therapy in conjunction with radiation therapy in treatment of lung cancer.
This work is supported by the CaNCURE program (grant #1CA174650-02), American Lung Association, Dana-Farber Cancer Institute and Brigham and Women's Hospital.
Citation Format: Ana G. Vazquez-Pagan, Paige Baldwin, Ravina M. Ashtaputre, Sijumon Kunjachan, Srinivas Sridhar, Rajiv Kumar, Ross Berbeco. Nanoparticle-mediated concomitant radiation dose amplification and PARP inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3710.
©2018 American Association for Cancer Research.@misc{baldwin2018targeted,
title = {Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment},
author = {Paige Baldwin and Rajiv Kumar and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells. These drugs are currently delivered orally, but Talazoparib, the most potent PARP inhibitor, exhibits greater toxicity than the others. Systemic administration of nanoparticles bypasses the first-pass metabolism of oral drugs and nanoparticles preferentially accumulate in tumors due to the leaky tumor vasculature. Additionally, nanoparticles can be actively targeted to tumors by conjugating different moieties such as antibodies that recognize overexpressed markers on the tumor cells. NanoTalazoparib (NanoTLZ) has been previously formulated and extensively characterized in breast, ovarian, and lung cancer models. Here we describe further characterization of NanoTLZ and the development of a next generation fluorescently labeled EPCAM targeted formulation of NanoTLZ for the treatment of triple negative breast cancer (TNBC).
Methods: Animals with orthotopic TNBC xenografts were injected with NanoTLZ and at various time points tumor biopsies were taken to assay tumor PAR levels. Blood was collected at various time points and plasma separated for drug extraction and quantification. Pharmacokinetic modeling is underway. Fluorescently labeled NanoTLZ was developed with the addition of Cy5, followed by further improvement via conjugation of anti-EPCAM antibodies. Targeting capability was assessed via laser scanning confocal microscopy after treatment of the TNBC cell line MDA-MB-231 with either non-targeted or targeted NanoTLZ. Therapeutic efficacy studies with targeted NanoTLZ alone and in combination with radiation are underway in an MDA-MB-231 xenograft model.
Results: Pharmacodynamics indicated PAR suppression in tumors within 30 minutes of NanoTLZ treatment. Tumor PAR levels began to increase 24 hours after a single dose but remained significantly lower than control levels up to 72 hours (P<0.005). Characterization of NanoTLZ after the addition of Cy5 and after anti-EPCAM targeting indicated that the formulation remained under 100 nm in diameter with a charge of ~10 mV and equivalent drug loading and release. Cy 5 labeling allowed for visualization of nanoparticle uptake and intracellular fluorescence was 70% greater in cells when treated with EPCAM targeted NanoTLZ compared to non-targeted.
Conclusions: The sustained release of Talazoparib from the nanoformulation decreases tumor PAR levels for up to 72 hours after a single dose, allowing for less frequent administration than the current daily regime used for oral Talazoparib. The targeted formulation of NanoTLZ shares the same physicochemical properties as the untargeted formulation, but is taken up much faster in vitro, suggesting it will allow for greater accumulation at the tumor site making it more effective than the previously tested untargeted NanoTLZ. Supported by ARMY/W81XWH-16-1-0731 and Rivkin Foundation.
Citation Format: Paige Baldwin, Rajiv Kumar, Srinivas Sridhar. Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3715.
©2018 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Animals with orthotopic TNBC xenografts were injected with NanoTLZ and at various time points tumor biopsies were taken to assay tumor PAR levels. Blood was collected at various time points and plasma separated for drug extraction and quantification. Pharmacokinetic modeling is underway. Fluorescently labeled NanoTLZ was developed with the addition of Cy5, followed by further improvement via conjugation of anti-EPCAM antibodies. Targeting capability was assessed via laser scanning confocal microscopy after treatment of the TNBC cell line MDA-MB-231 with either non-targeted or targeted NanoTLZ. Therapeutic efficacy studies with targeted NanoTLZ alone and in combination with radiation are underway in an MDA-MB-231 xenograft model.
Results: Pharmacodynamics indicated PAR suppression in tumors within 30 minutes of NanoTLZ treatment. Tumor PAR levels began to increase 24 hours after a single dose but remained significantly lower than control levels up to 72 hours (P<0.005). Characterization of NanoTLZ after the addition of Cy5 and after anti-EPCAM targeting indicated that the formulation remained under 100 nm in diameter with a charge of ~10 mV and equivalent drug loading and release. Cy 5 labeling allowed for visualization of nanoparticle uptake and intracellular fluorescence was 70% greater in cells when treated with EPCAM targeted NanoTLZ compared to non-targeted.
Conclusions: The sustained release of Talazoparib from the nanoformulation decreases tumor PAR levels for up to 72 hours after a single dose, allowing for less frequent administration than the current daily regime used for oral Talazoparib. The targeted formulation of NanoTLZ shares the same physicochemical properties as the untargeted formulation, but is taken up much faster in vitro, suggesting it will allow for greater accumulation at the tumor site making it more effective than the previously tested untargeted NanoTLZ. Supported by ARMY/W81XWH-16-1-0731 and Rivkin Foundation.
Citation Format: Paige Baldwin, Rajiv Kumar, Srinivas Sridhar. Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3715.
©2018 American Association for Cancer Research.@inproceedings{kunjachan2018best,
title = {BEST IN PHYSICS (THERAPY): Enhanced Drug Delivery by Nanoparticle and Radiation-Mediated Tumor Vascular Modulation},
author = {S Kunjachan and S Kotb and R Kumar and R Pola and M Pechar and F Gremse and R Taleei and F Trichard and V Motto-Ros and L Sancey and others},
year = {2018},
date = {2018-01-01},
booktitle = {MEDICAL PHYSICS},
volume = {45},
number = {6},
pages = {E535--E535},
organization = {WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{zhang2018nanoformulated,
title = {Nanoformulated Talazoparib enhances the efficacy and reduces the toxicity of this PARP inhibitor in a preclinical model of BRCA-deficient breast cancer},
author = {Di Zhang and Paige Baldwin and Srinivas Sridhar and Karen Liby},
year = {2018},
date = {2018-01-01},
journal = {The FASEB Journal},
volume = {32},
number = {1_supplement},
pages = {565--10},
publisher = {The Federation of American Societies for Experimental Biology},
abstract = {BRCA mutations are the leading cause of hereditary breast cancer. PARP inhibitors have shown promising activities in clinical trials for breast cancer by inducing synthetic lethality, particularly in patients with BRCA deficiency. Moreover, the utility of PARP inhibitors could potentially extend beyond BRCA mutations by targeting defects in homologous recombination, and thus impact up to 75% of triple negative breast cancer patients and 33% of breast cancer patients overall. However, conventional oral delivery of PARP inhibitors is hindered by limited bioavailability and significant off-target toxicities, thus compromising the therapeutic benefits and quality of life in patients. Therefore, we developed a new nanoparticle delivery system for PARP inhibitors and hypothesize that nanoformulated Talazoparib can enhance efficacy by increasing drug concentrations in the tumor and reduce off-target toxicities. The nanoparticle formulation includes polymer brushes to prolong the circulation time, enabling tumor accumulation through the enhanced permeability and retention effect. The therapeutic efficacy of Nano-Talazoparib (Nano-TLZ) was assessed after i.v. injection in Brca1Co/Co;MMTV-Cre; p53+/− mice with established tumors and compared to vehicle control (saline, i.v.), empty nanoparticles (i.v.), free Talazoparib (i.v.), and free Talazoparib (gavage). Treatment was started when the tumor was 4 mm in diameter and ended when the tumor size reached defined IACUC endpoints. Nano-TLZ significantly (p<0.05) prolonged the life span of BRCA deficient mice from 11.6±2.6 days with saline injection and 18.3±3.6 days with empty nanoparticles injection to 82.2±10.5 days with i.v. Nano-TLZ. Nano-TLZ induced growth arrest in 100% of the tumors and regression (> 50% reduction in tumor volume) in 80% of the tumors. Established tumors regressed more rapidly, and therefore progression free survival significantly improved in the nanoformulated Talazoparib group (p<0.05). Moreover, Nano-TLZ is better tolerated than free Talazoparib with no significant weight lost or alopecia. In a biomarker study following 10 days of treatment, Nano-TLZ increased double strand DNA breaks (γ-H2AX) and decreased proliferation (PCNA) compared to the saline controls. Interestingly, Nano-TLZ significantly (p<0.05) decreased myeloid derived suppressor cells in both the tumor (41.6±4.7% to 11.2±2.9%) and spleen (10.0±3.2% to 3.7±0.6%) compared to the saline control. Nano-TLZ also significantly (p<0.05) decreased the percentage of tumor-associated macrophages in the mammary gland from 7.4±2.0% in the saline control group to 2.5±0.2% in the Nano-TLZ group. The changes in immune populations suggest potential immunomodulatory effects of Talazoparib. These results demonstrate that the delivery of Talazoparib as a nanoformulation induces superior treatment outcomes with reduced off-target toxicity in BRCA deficient mice, and provides a novel delivery strategy for PARP inhibitors in patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{mitra2018comparative,
title = {The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation},
author = {Ronodeep Mitra and Ju Qiao and Sudharsan Madhavan and Gerard L O’Neil and Bailey Ritchie and Praveen Kulkarni and Srinivas Sridhar and Anne L van de Ven and Erica Cherry M Kemmerling and Craig Ferris and others},
year = {2018},
date = {2018-01-01},
journal = {Translational medicine communications},
volume = {3},
number = {1},
pages = {1--15},
publisher = {BioMed Central},
abstract = {Background and aims
Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.
Methods
Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.
Results
Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.
Conclusions
In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation.
Methods
Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts.
Results
Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group.
Conclusions
In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.@article{baldwin2018intraperitoneal,
title = {Intraperitoneal delivery of NanoOlaparib for disseminated late-stage cancer treatment},
author = {Paige Baldwin and Anders W Ohman and Shifalika Tangutoori and Daniela M Dinulescu and Srinivas Sridhar},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
pages = {8063},
publisher = {Dove Press},
abstract = {Background
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.
Methods
The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.
Results
Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.
Conclusion
NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
PARP inhibitors, such as Olaparib, have advanced the treatment of ovarian cancer by providing patients with an effective and molecularly-targeted maintenance therapy. However, all orally-administered drugs, including Olaparib, must undergo first-pass metabolism. In contrast, a nanoparticle delivery system has the advantage of administering Olaparib directly into the peritoneal cavity for local treatment. Consequently, we sought to optimize the sustained-release formulation NanoOlaparib, previously deemed effective as an intravenous solid tumor treatment, for the local treatment of disseminated disease via intraperitoneal (i.p.) therapy.
Methods
The tumor cell line 404, which was derived from a Brca2−/−, Tp53−/−, Pten−/− genetically engineered mouse model, exhibited high sensitivity to Olaparib in vitro. It was chosen for use in developing an i.p. spread xenograft for testing nanotherapy efficacy in vivo. NanoOlaparib as a monotherapy or in combination with cisplatin was compared to oral Olaparib alone or in combination using two different dose schedules. A pilot biodistribution study was performed to determine drug accumulation in various organs following i.p. administration.
Results
Daily administration of NanoOlaparib reduced tumor growth and decreased the variability of the treatment response observed with daily oral Olaparib administration. However, systemic toxicity was observed in both the NanoOlaparib and vehicle (empty nanoparticle) treated groups. Scaling back the administration to twice weekly was well tolerated up to 100 mg/kg but reduced the effect on tumor growth. Biodistribution profiles indicated that NanoOlaparib began accumulating in tissues within an hour of administration and persisted for at least 72 hours after a single dose, exiting the peritoneal cavity faster than expected.
Conclusion
NanoOlaparib must be modified for use against disseminated disease. Future avenues to develop NanoOlaparib as an i.p. therapy include a modified surface-coating to retain it in the peritoneal cavity and prevent entry into systemic circulation, in addition to targeting moieties for localization in tumor cells.@misc{faegh2018sensor,
title = {Sensor system utilizing piezoelectric microcantilever coupled with resonating circuit},
author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},
year = {2018},
date = {2018-00-01},
abstract = {An interchangeable sensor system is described, including: a microcantilever including a beam anchored at a first end, the beam being free to vibrate on another end, wherein a piezoelectric layer is deposited on a surface of the beam; an input configured to receive a voltage from a voltage source for applying voltage to the piezoelectric layer; and a resonating circuit including: the piezoelectric layer, configured as a capacitor of the resonant circuit; and one or more additional electrical elements; wherein the voltage source is configured to apply a first AC voltage under a first condition for actuating the microcantilever at a first mechanical resonating frequency of the microcantilever and a second AC voltage under a second condition for actuating the microcantilever at a second electrical resonating frequency of the resonating circuit. Method of using the sensor system is also described.},
note = {US Patent 9,921,226},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{wilfred2018biomaterials,
title = {Biomaterials for combined radiotherapy and immunotherapy of cancer},
author = {NGWA Wilfred and Rajiv Kumar and Gerassimos Makrigiorgos and Srinivas Sridhar and Stephanie Dougan},
year = {2018},
date = {2018-00-01},
abstract = {Compositions and methods for the radiological and immunotherapeutic treatment of cancer are provided. Metallic nanoparticles conjugated with an immunoadjuvant are dispersed within a biodegradable polymer matrix that can be implanted in a patient and released gradually. The implant may be configured as, or be a component of, brachytherapy spacers and applicators, or radiotherapy fiducial markers. The composition may be combined with marginless radiotherapy, allowing for lower doses of radiation and enhancing the immune response against cancer, including at non-irradiated sites.},
note = {US Patent App. 15/752,099},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{barlow2017high,
title = {High throughput microencapsulation of Bacillus subtilis in semi-permeable biodegradable polymersomes for selenium remediation},
author = {Jacob Barlow and Kevin Gozzi and Chase P Kelley and Benjamin M Geilich and Thomas J Webster and Yunrong Chai and Srinivas Sridhar and Anne L van de Ven},
year = {2017},
date = {2017-01-01},
journal = {Applied microbiology and biotechnology},
volume = {101},
number = {1},
pages = {455--464},
publisher = {Springer Berlin Heidelberg},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{geilich2017superparamagnetic,
title = {Superparamagnetic iron oxide-encapsulating polymersome nanocarriers for biofilm eradication},
author = {Benjamin M Geilich and Ilia Gelfat and Srinivas Sridhar and Anne L van de Ven and Thomas J Webster},
year = {2017},
date = {2017-01-01},
journal = {Biomaterials},
volume = {119},
pages = {78--85},
publisher = {Elsevier},
abstract = {The rising prevalence and severity of antibiotic-resistant biofilm infections poses an alarming threat to public health worldwide. Here, biocompatible multi-compartment nanocarriers were synthesized to contain both hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) and the hydrophilic antibiotic methicillin for the treatment of medical device-associated infections. SPION co-encapsulation was found to confer unique properties, enhancing both nanocarrier relaxivity and magneticity compared to individual SPIONs. These iron oxide-encapsulating polymersomes (IOPs) penetrated 20 μm thick Staphylococcus epidermidis biofilms with high efficiency following the application of an external magnetic field. Three-dimensional laser scanning confocal microscopy revealed differential bacteria death as a function of drug and SPION loading. Complete eradication of all bacteria throughout the biofilm thickness was achieved using an optimized IOP formulation containing 40 μg/mL SPION and 20 μg/mL of methicillin. Importantly, this formulation was selectively toxic towards methicillin-resistant biofilm cells but not towards mammalian cells. These novel iron oxide-encapsulating polymersomes demonstrate that it is possible to overcome antibiotic-resistant biofilms by controlling the positioning of nanocarriers containing two or more therapeutics.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{paro2017abstract,
title = {Abstract B44: Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer},
author = {Autumn D Paro and Ilan Shanmugam and Anne van de Ven and Rajiv Kumar and Thomas J Webster and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: The objective of this project is to study the biological pathways activated in irradiated pancreatic cancer cells pre-treated with gold nanoparticles. Metallic nanoparticles emit Auger electrons and photoelectrons upon exposure to X-rays. When selectively delivered to tumors, these nanoparticles can locally enhance the effects of radiation therapy. Previous in vitro work has primarily studied the effectiveness of nanoparticle-enhanced therapy, without elucidating the underlying biological mechanisms. Understanding the biological mechanisms (such as changes in gene expression) of how nanoparticles enhance radiation therapy can help in the further design of more effective nanoparticles.
Methods: Gold nanoparticle sensitization was tested using a human based pancreatic cancer cell line, Capan-1. Nanoparticle toxicity was tested using a combination of MTS and Alamar Blue assays after 24 hours of treatment. Gene expression was tested using immunofluorescence and western blot techniques. Cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation. Cells were then harvested at various time points to determine how gene expression changes over time. Radiosensitization was carried out using a clonogic cell survival assay where cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation and then re-plated at various densities 4 hours post radiation, and allowed to incubate for 14 days. Statistical differences were determined using ANOVA followed by student t-tests.
Results: The MTS and Alamar blue assays showed low gold nanoparticle toxicity towards cells up to a dose of 1mg for Capan-1 cells. Capan-1 cells pretreated with 0.8 mg gold nanoparticles for 24 hours prior to radiation showed lower cell survival than cells only treated with radiation. Western blots and immunofluorescence data showed that certain genes, such as γ-H2AX, were upregulated when pretreated with gold nanoparticles and irradiated compared to cells treated with radiation alone. It was also shown that γ-H2AX expression peaked around 30 minutes post radiation and then returned to basal levels after 24 hours.
Conclusions: Capan-1 cells experience more DNA damage when pretreated with gold nanoparticles than when only treated with radiation. γ-H2AX, which is a DNA damage-related protein, was upregulated in the combined dose showing that there was more DNA damage in the combined treatment. It was also shown that protein and gene expression analysis needs to be carried out at various time points post radiation to obtain a better understanding of the mechanisms involved in radiation induced damage to pancreatic cancer cells.
Supported by NSF-DGE- 0965843 and CA188833-02.
Citation Format: Autumn D. Paro, Ilan Shanmugam, Anne van de Ven, Rajiv Kumar, Thomas J. Webster, Srinivas Sridhar. Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B44.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Gold nanoparticle sensitization was tested using a human based pancreatic cancer cell line, Capan-1. Nanoparticle toxicity was tested using a combination of MTS and Alamar Blue assays after 24 hours of treatment. Gene expression was tested using immunofluorescence and western blot techniques. Cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation. Cells were then harvested at various time points to determine how gene expression changes over time. Radiosensitization was carried out using a clonogic cell survival assay where cells were pretreated with 0.8 mg gold nanoparticles 24 hours prior to radiation and then re-plated at various densities 4 hours post radiation, and allowed to incubate for 14 days. Statistical differences were determined using ANOVA followed by student t-tests.
Results: The MTS and Alamar blue assays showed low gold nanoparticle toxicity towards cells up to a dose of 1mg for Capan-1 cells. Capan-1 cells pretreated with 0.8 mg gold nanoparticles for 24 hours prior to radiation showed lower cell survival than cells only treated with radiation. Western blots and immunofluorescence data showed that certain genes, such as γ-H2AX, were upregulated when pretreated with gold nanoparticles and irradiated compared to cells treated with radiation alone. It was also shown that γ-H2AX expression peaked around 30 minutes post radiation and then returned to basal levels after 24 hours.
Conclusions: Capan-1 cells experience more DNA damage when pretreated with gold nanoparticles than when only treated with radiation. γ-H2AX, which is a DNA damage-related protein, was upregulated in the combined dose showing that there was more DNA damage in the combined treatment. It was also shown that protein and gene expression analysis needs to be carried out at various time points post radiation to obtain a better understanding of the mechanisms involved in radiation induced damage to pancreatic cancer cells.
Supported by NSF-DGE- 0965843 and CA188833-02.
Citation Format: Autumn D. Paro, Ilan Shanmugam, Anne van de Ven, Rajiv Kumar, Thomas J. Webster, Srinivas Sridhar. Biological mechanisms involved in nanoparticle-enhanced radiation therapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B44.
©2016 American Association for Cancer Research.@misc{baldwin2017abstract,
title = {Abstract B29: Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib},
author = {Paige Baldwin and Anders Ohman and Jodi Belz and Jeremy Thong and Noelle Castilla Ojo and Karen Liby and Daniela Dinulescu and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents. Here we report the development of two different delivery techniques including nanoformulations of Olaparib and Talazoparib and a biodegradable implant for localized delivery of Talazoparib. The nanoformulations allow for intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities and the implant provides a sustained release for intratumoral delivery to enhance the dose at the tumor site thereby limiting systemic toxicity.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment.
Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843.
Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment.
Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843.
Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.
©2016 American Association for Cancer Research.@misc{codi2017abstract,
title = {Abstract B22: Quantitative tumor imaging using magnetic nanoparticles},
author = {Gharagouzloo Codi and Ju Qiao and Liam Timms and Anne van de Ven and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: We have developed a new method of Quantitative MRI named QUTE-CE MRI that yields images of the vasculature with unparalleled clarity and definition and is quantitative. QUTE-CE MRI can produce contrast enhanced magnetic resonance angiograms (CE-MRA) using super paramagnetic iron-oxide nanoparticle (SPION), including the FDA approved ferumoxytol, with high contrast in cardiovascular, cerebral, and tumor imaging.
Based upon principles of magnetic nanoparticle interactions with neighboring water molecules, the method achieves robust, reproducible results by utilizing rapid signal acquisition at ultra-short time-to-echo (UTE) to produce positive-contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation (SPGR) is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters.
Methods: All animal experiments were conducted in accordance with the Northeastern University Division of Laboratory Animal Medicine and Institutional Animal Care and Use Committee. MRI images were obtained at ambient temperature (∼25°C) using a Bruker Biospec 7.0T/20-cm USR horizontal magnet (Bruker, Billerica, Massachusetts, USA) equipped with a 20-G/cm magnetic field gradient insert (ID =12 cm, Bruker) and the same quadrature 300 MHz, 30 mm Mouse MRI coil was used for all in vivo work as previously utilized for mouse experiments in Section 3.8 (Animal Imaging Research, LLC, Holden, Massachusetts, USA).
PC 3 cells were injected into the right flank of immunocompromised FoxNu1 mice (n=5, Charles River Laboratories). After tumors reached about 0.5-1.0cm3, animals underwent three separate imaging sessions: Session 1 - pre-contrast T1, T2 and QUTE-CE measurements, Session 2 - immediate post-contrast QUTE-CE measurement and Session 3 - 24h post-contrast T1, T2 and QUTE-CE measurements. For contrast, 100μl of ferumoxytol diluted to 6mg/ml was injected i.v. to render a blood concentration of ~200μg/ml Fe (2x clinical dose).
Results: Contrary to more standard MRI techniques, QUTE-CE pre-contrast images render a nearly homogenous signal with a Gaussian distribution in the tumor. The immediate post-contrast images render the vasculature clearly and skew the distribution of voxels within the whole tumor to the left, however also increases the overall mean of the signal intensity because the movement of voxels within the tumor is to the right, leaving a long bright tail with the brightest voxels represented by those containing 100% blood. 24h after the initial administration of ferumoxytol the vasculature is no longer visible, but the locations within the tumor that have passively accumulated SPIONs resulting from the EPR effect becomes apparent. While the distribution of voxels within the tumor becomes less skewed, the overall shape is still slightly skewed to the left and the mean of the distribution has moved to the right. Nanoparticle accumulation in the post-contrast image is heterogeneous and unambiguous.
Angiography and TBV in tumors Assuming a partial 2-volume model of blood and tissue, we determine the tumor blood volume (TBV) across the entire tumor volume. The resultant TBV heatmaps show a clear range of TBV values are apparent, delineating areas of the tissue with high contrast in regard to overall vascular health, including apparently necrotic tissue.
Nanoparticle accumulation Next, a unique feature of the methodology to produce high-contrast images of purely T1-weighted signal is employed to unambiguously delineate nanoparticle accumulation in a PC3 subcutaneous tumor model with ferumoxytol accumulation 24 hours after just one dose. From this, contrast efficiency was produced compared to standard techniques with the additional benefit that pre-contrast images are not necessitated. A major advantage of delineating SPION accumulation using QUTE-CE, compared to ΔT2 or ΔT1 imaging, is that the post-contrast image contains sufficient information for nanoparticle localization, eliminating the need for pre-contrast images.
Conclusion: QUTE-CE MRI exploits physical principles of magnetic relaxation modulated by SPIONs to achieve quantitative MRI yielding exceptional vascular images. This ability to longitudinally quantify blood pool CA concentration is unique to the QUTE-CE method, and makes QUTE-CE MRI competitive with nuclear imaging. Quantitative tumor blood volume distributions are obtained at short times, while nanoparticle accumulation maps are obtained at long times. QUTE-CE MRI is a new method that can be used to study tumor properties longitudinally. The technique is immediately translatable to the clinic using the FDA approved contrast agent ferumoxytol and is expected to have a major impact on clinical tumor imaging.
Work supported by NSF-DGE- 0965843.
Citation Format: Gharagouzloo Codi, Ju Qiao, Liam Timms, Anne van de Ven, Srinivas Sridhar. Quantitative tumor imaging using magnetic nanoparticles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B22.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Based upon principles of magnetic nanoparticle interactions with neighboring water molecules, the method achieves robust, reproducible results by utilizing rapid signal acquisition at ultra-short time-to-echo (UTE) to produce positive-contrast images with pure T1 weighting and little T2* decay. The spoiled gradient echo equation (SPGR) is used to transform UTE intensities directly into concentration using experimentally determined relaxivity constants and image acquisition parameters.
Methods: All animal experiments were conducted in accordance with the Northeastern University Division of Laboratory Animal Medicine and Institutional Animal Care and Use Committee. MRI images were obtained at ambient temperature (∼25°C) using a Bruker Biospec 7.0T/20-cm USR horizontal magnet (Bruker, Billerica, Massachusetts, USA) equipped with a 20-G/cm magnetic field gradient insert (ID =12 cm, Bruker) and the same quadrature 300 MHz, 30 mm Mouse MRI coil was used for all in vivo work as previously utilized for mouse experiments in Section 3.8 (Animal Imaging Research, LLC, Holden, Massachusetts, USA).
PC 3 cells were injected into the right flank of immunocompromised FoxNu1 mice (n=5, Charles River Laboratories). After tumors reached about 0.5-1.0cm3, animals underwent three separate imaging sessions: Session 1 - pre-contrast T1, T2 and QUTE-CE measurements, Session 2 - immediate post-contrast QUTE-CE measurement and Session 3 - 24h post-contrast T1, T2 and QUTE-CE measurements. For contrast, 100μl of ferumoxytol diluted to 6mg/ml was injected i.v. to render a blood concentration of ~200μg/ml Fe (2x clinical dose).
Results: Contrary to more standard MRI techniques, QUTE-CE pre-contrast images render a nearly homogenous signal with a Gaussian distribution in the tumor. The immediate post-contrast images render the vasculature clearly and skew the distribution of voxels within the whole tumor to the left, however also increases the overall mean of the signal intensity because the movement of voxels within the tumor is to the right, leaving a long bright tail with the brightest voxels represented by those containing 100% blood. 24h after the initial administration of ferumoxytol the vasculature is no longer visible, but the locations within the tumor that have passively accumulated SPIONs resulting from the EPR effect becomes apparent. While the distribution of voxels within the tumor becomes less skewed, the overall shape is still slightly skewed to the left and the mean of the distribution has moved to the right. Nanoparticle accumulation in the post-contrast image is heterogeneous and unambiguous.
Angiography and TBV in tumors Assuming a partial 2-volume model of blood and tissue, we determine the tumor blood volume (TBV) across the entire tumor volume. The resultant TBV heatmaps show a clear range of TBV values are apparent, delineating areas of the tissue with high contrast in regard to overall vascular health, including apparently necrotic tissue.
Nanoparticle accumulation Next, a unique feature of the methodology to produce high-contrast images of purely T1-weighted signal is employed to unambiguously delineate nanoparticle accumulation in a PC3 subcutaneous tumor model with ferumoxytol accumulation 24 hours after just one dose. From this, contrast efficiency was produced compared to standard techniques with the additional benefit that pre-contrast images are not necessitated. A major advantage of delineating SPION accumulation using QUTE-CE, compared to ΔT2 or ΔT1 imaging, is that the post-contrast image contains sufficient information for nanoparticle localization, eliminating the need for pre-contrast images.
Conclusion: QUTE-CE MRI exploits physical principles of magnetic relaxation modulated by SPIONs to achieve quantitative MRI yielding exceptional vascular images. This ability to longitudinally quantify blood pool CA concentration is unique to the QUTE-CE method, and makes QUTE-CE MRI competitive with nuclear imaging. Quantitative tumor blood volume distributions are obtained at short times, while nanoparticle accumulation maps are obtained at long times. QUTE-CE MRI is a new method that can be used to study tumor properties longitudinally. The technique is immediately translatable to the clinic using the FDA approved contrast agent ferumoxytol and is expected to have a major impact on clinical tumor imaging.
Work supported by NSF-DGE- 0965843.
Citation Format: Gharagouzloo Codi, Ju Qiao, Liam Timms, Anne van de Ven, Srinivas Sridhar. Quantitative tumor imaging using magnetic nanoparticles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B22.
©2016 American Association for Cancer Research.@misc{van2017abstract,
title = {Abstract B48: Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John Clohessy and Houari Korideck and Mike G Makrigiorgos and Robert Cormack and others},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Prostate cancers with PTEN deletions are promising candidates for DNA repair inhibitors such as olaparib and talazoparib. Here we show that radiation-resistant cells and tumors derived from Ptenpc-/-;Trp53pc-/- mice are rendered radiation-sensitive following pre-treatment with liposomal nanoOlaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to nanoformulated Olaparib alone. In animals, twice-weekly intravenous administration of nanoOlaparib alone results in significant tumor growth inhibition. When nanoOlaparib is administered prior to radiation, we find that a single dose of radiation is sufficient to increase mouse survival time by as much as 10 weeks (study duration = 13 weeks). Using ferumoxytol as a surrogate nanoparticle, magnetic resonance imaging (MRI) studies revealed that nanoOlaparib administration enhances the ability of nanoparticles to accumulate in tumors. Compared to untreated and radiation-only controls, nanoOlaparib-treated tumors showed 18-fold higher nanoparticle accumulation, suggesting that the in vivo efficacy of nanoOlaparib may be potentiated by its ability to enhance its own accumulation in tumors.
Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: Anne L. van de Ven, Shifalika Tangutoori, Paige Baldwin, Ju Qiao, Codi Gharagouzloo, Nina Seitzer, John Clohessy, Houari Korideck, G. Mike Makrigiorgos, Robert Cormack, Pier Paolo Pandolfi, Srinivas Sridhar. Prostate cancer pre-treatment with nanoformulated Olaparib overcomes radiation resistance. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B48.
©2016 American Association for Cancer Research.@misc{kumar2017abstract,
title = {Abstract B41: Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy},
author = {Rajiv Kumar and Wilfred Ngwa and Vinit Joshi and Sijumon Kunjachan and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and the unique properties associated with gold nanoparticles makes them as potent radiosensitizers for enhancing Radiotherapy (RT) treatments. The interaction of high Z materials with the X-rays results in photoelectric absorption which leads to generation of photoelectrons. These low energy photoelectrons can deliver lethal energy in the close proximity. The success of cancer radiation therapy relies heavily on the effective delivery of radiation dose to the tumor site sparing the surrounding normal tissues. To overcome the limitations associated with increasing the radiation dose, due to normal tissue toxicities, the feasibility of radiosensitizing the tumor using gold nanoparticles provide a promising alternative. Targeting gold nanoparticles based formulations to the tumor prior to radiation therapy will result in radiation dose enhancement, by generating secondary photoelectrons, locally inside the tumor and thereby minimizing the dose dependent toxicity to non-specific neighboring tissues. Here, we have developed different Gold nanoparticles based formulations to locally radiosensitize the tumor cells in three different cancer models.
For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining.
For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway.
For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform.
This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining.
For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway.
For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform.
This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.
©2016 American Association for Cancer Research.@misc{belz2017abstract,
title = {Abstract B30: Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.
©2016 American Association for Cancer Research.@incollection{belz2017radiosensitizing,
title = {Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer},
author = {Jodi Belz and Noelle Castilla-Ojo and Srinivas Sridhar and Rajiv Kumar},
year = {2017},
date = {2017-01-01},
booktitle = {Cancer Nanotechnology},
pages = {403--409},
publisher = {Humana Press, New York, NY},
abstract = {The applications of nanoparticles in oncology include enhanced drug delivery, efficient tumor targeting, treatment monitoring, and diagnostics. The “theranostic properties” associated with nanoparticles have shown enhanced delivery of chemotherapeutic drugs with superior imaging capabilities and minimal toxicities. In conventional chemotherapy, only a fraction of the administered drug reaches the tumor site or cancer cells. For successful translation of these formulations, it is imperative to evaluate the design and properties of these nanoparticles. Here, we describe the design of ultra-small silica nanoparticles to encapsulate a radiosensitizing drug for combined chemoradiation therapy. The small size of nanoparticles allows for better dispersion and uptake of the drug within the highly vascularized tumor tissue. Silica nanoparticles are synthesized using an oil-in-water microemulsion method. The microemulsion method provides a robust synthetic route in which the inner hydrophobic core is used to encapsulate chemotherapy drug, docetaxel while the outer hydrophilic region provides dispersibility of the synthesized nanoparticles in an aqueous environment. Docetaxel is commonly used for treatment of resistant or metastatic prostate cancer, and is known to have radiosensitizing properties. Here, we describe a systematic approach for synthesizing these theranostic nanoparticles for application in prostate cancer.},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
@incollection{baldwin2017generation,
title = {Generation of Dose--Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations},
author = {Paige Baldwin and Shifalika Tangutoori and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
booktitle = {Cancer Nanotechnology},
pages = {337--342},
publisher = {Humana Press, New York, NY},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
@article{guthier2017focal,
title = {Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Christian V Guthier and Anthony V D'Amico and Martin T King and Paul L Nguyen and Peter F Orio and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2017},
date = {2017-01-01},
journal = {Brachytherapy},
volume = {16},
number = {3},
pages = {S115},
publisher = {Elsevier},
abstract = {In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …@article{van2017nanoformulation,
title = {Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John G Clohessy and Mike G Makrigiorgos and Robert Cormack and Pier Paolo Pandolfi and others},
year = {2017},
date = {2017-01-01},
journal = {Molecular cancer therapeutics},
volume = {16},
number = {7},
pages = {1279--1289},
publisher = {American Association for Cancer Research},
abstract = {The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{baldwin2017abstractb,
title = {Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER},
author = {Paige Baldwin and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {PURPOSE: PARP inhibitor therapy for ovarian cancer exploits the concept of synthetic lethality by taking advantage of defects in DNA damage repair pathways. Currently Olaparib is the only FDA-approved PARP inhibitor and is available as an oral dosage, which has plenty of advantages, but requires the drug to undergo first pass metabolism, inactivating a significant fraction of the dose. We have developed a nanoparticle delivery system to allow for local delivery of Olaparib directly to the intraperitoneal cavity.
METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging.
RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment.
CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy.
Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-080.
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging.
RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment.
CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy.
Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-080.
©2017 American Association for Cancer Research.@misc{baldwin2017nanoformulated,
title = {Nanoformulated Talazoparib and Olaparib for enhanced delivery},
author = {Paige Baldwin and Rajiv Kumar and Edward Favours and Karen Liby and Raushan Kurmasheva and David Kozono and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors such as Talazoparib and Olaparib exploit deficiencies in DNA repair pathways, making them attractive candidates for treatment of a number of different cancers. These drugs are particularly effective when used in combination with other DNA damaging agents such as chemotherapeutics and radiation therapy. Combination trials, however, have resulted in severe toxicities, necessitating either dose reduction or delay. Dose reduction leads to suboptimal dosing and provides little therapeutic benefit compared to monotherapy. Systemically administered nanoparticles offer a more effective way to selectively accumulate drugs in tumors and bypass toxicities associated with oral delivery. We have developed nanoparticle delivery systems for both Olaparib and Talazoparib in order to improve tumor accumulation while bypassing the toxicity associated with oral administration.
Methods: Lipid nanoformulations of Olaparib and Talazoparib have been developed and characterized in regard to size, surface charge, drug loading, release, and stability. NanoTalazoparib has been tested in vitro in breast cancer cell lines including W0069, W780, and HCC1937 which exhibit BRCA1 and 2 mutations, and NanoOlaparib in the lung cancer cell line Calu-6 which also has a defective FA-BRCA pathway. Mice have been treated with NanoOlaparib and NanoTalazoparib alone and in combination with radiation or temozolomide in order to evaluate toxicity. Therapeutic efficacy studies are currently underway.
Results: The nanoformulations have been formulated to encapsulate a clinically relevant dose of either Talazoparib or Olaparib and release at 37°C over a period of days, while remaining stable during storage at 4°C. In vitro, both nanoformulations show the same activity as free drug with IC50s in the nanomolar range for these cell lines with varying deficiencies in the BRCA pathway. Mice have shown no appreciable weight loss during treatment with either nanoformulation alone or in combination with other treatment modalities.
Conclusion: Nanoformulations of Talazoparib and Olaparib have been developed and characterized to demonstrate activity in vitro and tolerable doses in vivo. We have found that mice tolerate NanoTalazoparib at higher doses when combined with Temozolomide than when given oral Talazoparib. The sustained release from the nanoparticles allows for the nanoformulation to be administered less often than the daily administration for oral drug and the improved tolerability opens the door for combination therapy with both chemotherapeutics and radiation therapy. Therapeutic efficacy studies are underway and we expect that as a monotherapy NanoTalazoparib will be more effective at lower doses than oral Talazoparib, based on the longer circulation time and more selective accumulation in tumors. We also anticipate that combination therapy will be more effective with the nanoformulation, as the maximum tolerated dose is higher than that of the oral drug.
Citation Format: Paige Baldwin, Rajiv Kumar, Edward Favours, Karen Liby, Raushan Kurmasheva, David Kozono, Srinivas Sridhar. Nanoformulated Talazoparib and Olaparib for enhanced delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2017-3100
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Lipid nanoformulations of Olaparib and Talazoparib have been developed and characterized in regard to size, surface charge, drug loading, release, and stability. NanoTalazoparib has been tested in vitro in breast cancer cell lines including W0069, W780, and HCC1937 which exhibit BRCA1 and 2 mutations, and NanoOlaparib in the lung cancer cell line Calu-6 which also has a defective FA-BRCA pathway. Mice have been treated with NanoOlaparib and NanoTalazoparib alone and in combination with radiation or temozolomide in order to evaluate toxicity. Therapeutic efficacy studies are currently underway.
Results: The nanoformulations have been formulated to encapsulate a clinically relevant dose of either Talazoparib or Olaparib and release at 37°C over a period of days, while remaining stable during storage at 4°C. In vitro, both nanoformulations show the same activity as free drug with IC50s in the nanomolar range for these cell lines with varying deficiencies in the BRCA pathway. Mice have shown no appreciable weight loss during treatment with either nanoformulation alone or in combination with other treatment modalities.
Conclusion: Nanoformulations of Talazoparib and Olaparib have been developed and characterized to demonstrate activity in vitro and tolerable doses in vivo. We have found that mice tolerate NanoTalazoparib at higher doses when combined with Temozolomide than when given oral Talazoparib. The sustained release from the nanoparticles allows for the nanoformulation to be administered less often than the daily administration for oral drug and the improved tolerability opens the door for combination therapy with both chemotherapeutics and radiation therapy. Therapeutic efficacy studies are underway and we expect that as a monotherapy NanoTalazoparib will be more effective at lower doses than oral Talazoparib, based on the longer circulation time and more selective accumulation in tumors. We also anticipate that combination therapy will be more effective with the nanoformulation, as the maximum tolerated dose is higher than that of the oral drug.
Citation Format: Paige Baldwin, Rajiv Kumar, Edward Favours, Karen Liby, Raushan Kurmasheva, David Kozono, Srinivas Sridhar. Nanoformulated Talazoparib and Olaparib for enhanced delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2017-3100
©2017 American Association for Cancer Research.@misc{baig2017nanoformulation,
title = {Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts},
author = {Nabeela Baig and Rostislav Likhotvorik and Paige Baldwin and Srinivas Sridhar and Raushan Kurmasheva},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Ewing Family of tumors (EFT) comprises the fourth most common highly malignant childhood cancer. Although sustained event-free survival (EFS) can be achieved with intensive chemo-radiation therapy for patients with local-regional disease, this therapy is relatively ineffective in the treatment of metastatic disease with EFS of 12% at 5 years. Ewing sarcoma is characterized by a reciprocal translocation between chromosomes 11 and 22 that encodes a chimeric oncoprotein resulting from the fusion of EWSR1 to the FLI1 transcription factor in ~85% of tumors. Therapy for patients with EFT comprises surgery, intensive use of cytotoxic agents and radiation therapy. Dose intensification and dose compression has resulted in some improvement in outcome, but patents with advanced or metastatic disease at diagnosis still represent a challenge. Further, patients alive at 5 years from diagnosis still have a high probability of subsequent relapse. Further, long-term consequences of treatment included cardiac dysfunction, and secondary malignancies. Thus, more effective and less toxic therapies are required to treat patients with advanced disease.
Our studies, as part of the Pediatric Preclinical Testing Program (PPTP), identified the combination of the PARP inhibitor, talazoparib, with the DNA damaging agent temozolomide, as being highly synergistic in xenograft models of Ewing sarcoma, but not against other tumor types. In this study 5 of 10 Ewing tumor xenografts models showed dramatic regressions to the combination, while administered as single agents neither talazoparib or temozolomide were active. We have studied the talazoparib-temozolomide synergy in vitro, and results indicate that in models where there is no synergy as xenografts, the cell lines have either intrinsic resistance to talazoparib, temozolomide or both drugs. In mice, and in the clinical trial (NCT02116777), the talazoparib-temozolomide combination is toxic requiring a reduction in temozolomide dose to ~15% of its single maximum-tolerated dose.
We are exploring the use of nanoparticle-formulated talazoparib (npTLZ) developed by Nanomaterials Synthesis Laboratory at Northeastern University without tumor targeting or with antibody-mediated targeting to increase the tumor-drug delivery, reduce normal tissue toxicity (mainly thrombocytopenia), and potentially allow escalation of temozolomide dose. In the PPTP study, the MTD for temozolomide combined with free talazoparib (0.25 mg/kg PO BID daily x 5) was 12 mg/kg. Our recent data showed no toxicity of temozolomide at 66 mg/kg (PO daily x 5) in mice treated with npTLZ (0.5 mg/kg IV daily x 5), suggesting that npTLZ does not potentiate TMZ toxicity to normal mouse tissues. We anticipate that nanoparticle delivery of talazoparib combined with temozolomide will allow reduced toxicity while increasing the response rate for this combination in preclinical models of Ewing sarcoma.
Citation Format: Nabeela Baig, Rostislav Likhotvorik, Paige Baldwin, Srinivas Sridhar, Raushan Kurmasheva. Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5054. doi:10.1158/1538-7445.AM2017-5054
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Our studies, as part of the Pediatric Preclinical Testing Program (PPTP), identified the combination of the PARP inhibitor, talazoparib, with the DNA damaging agent temozolomide, as being highly synergistic in xenograft models of Ewing sarcoma, but not against other tumor types. In this study 5 of 10 Ewing tumor xenografts models showed dramatic regressions to the combination, while administered as single agents neither talazoparib or temozolomide were active. We have studied the talazoparib-temozolomide synergy in vitro, and results indicate that in models where there is no synergy as xenografts, the cell lines have either intrinsic resistance to talazoparib, temozolomide or both drugs. In mice, and in the clinical trial (NCT02116777), the talazoparib-temozolomide combination is toxic requiring a reduction in temozolomide dose to ~15% of its single maximum-tolerated dose.
We are exploring the use of nanoparticle-formulated talazoparib (npTLZ) developed by Nanomaterials Synthesis Laboratory at Northeastern University without tumor targeting or with antibody-mediated targeting to increase the tumor-drug delivery, reduce normal tissue toxicity (mainly thrombocytopenia), and potentially allow escalation of temozolomide dose. In the PPTP study, the MTD for temozolomide combined with free talazoparib (0.25 mg/kg PO BID daily x 5) was 12 mg/kg. Our recent data showed no toxicity of temozolomide at 66 mg/kg (PO daily x 5) in mice treated with npTLZ (0.5 mg/kg IV daily x 5), suggesting that npTLZ does not potentiate TMZ toxicity to normal mouse tissues. We anticipate that nanoparticle delivery of talazoparib combined with temozolomide will allow reduced toxicity while increasing the response rate for this combination in preclinical models of Ewing sarcoma.
Citation Format: Nabeela Baig, Rostislav Likhotvorik, Paige Baldwin, Srinivas Sridhar, Raushan Kurmasheva. Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5054. doi:10.1158/1538-7445.AM2017-5054
©2017 American Association for Cancer Research.@article{hachani2017assessing,
title = {Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging},
author = {Roxanne Hachani and Martin A Birchall and Mark W Lowdell and Georgios Kasparis and Le D Tung and Bella B Manshian and Stefaan J Soenen and Willy Gsell and Uwe Himmelreich and Codi A Gharagouzloo and others},
year = {2017},
date = {2017-01-01},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {1--14},
publisher = {Nature Publishing Group},
abstract = {Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging (MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T2 - weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T2-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T2-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gharagouzloo2017quantitative,
title = {Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function},
author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Neuroimage},
volume = {163},
pages = {24--33},
publisher = {Academic Press},
abstract = {A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{belz2017sustained,
title = {Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer},
author = {Jodi E Belz and Rajiv Kumar and Paige Baldwin and Noelle Castilla Ojo and Ana S Leal and Darlene B Royce and Di Zhang and Anne L van de Ven and Karen T Liby and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Theranostics},
volume = {7},
number = {17},
pages = {4340},
publisher = {Ivyspring International Publisher},
abstract = {Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{gharagouzloo2017quantitativeb,
title = {Quantitative magnetic resonance imaging of the vasculature},
author = {Codi Gharagouzloo and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
abstract = {A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided. The technique can be used to accurately measure contrast agent concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of cerebral blood volume on a voxel -by- voxel basis.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@inproceedings{belz2017sustainedb,
title = {Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
booktitle = {CANCER RESEARCH},
volume = {77},
organization = {AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~…},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.@misc{kumar2017biopolymer,
title = {Biopolymer-Nanoparticle Composite Implant for Tumor Cell Tracking},
author = {Rajiv Kumar and Srinivas Sridhar and NGWA Wilfred and Robert Cormack and Gerassimos Makrigiorgos},
year = {2017},
date = {2017-00-01},
abstract = {A method of detecting migration of tumor cells is provided by implanting in a region of tumor cells one or more implants having a matrix material of a biocompatible and biodegradable polymer, and a plurality of nanoparticles dispersed within the matrix material and functionalized to bind tumor cells. Nanoparticles bound to the tumor cells that have migrated out of the region can be detected by various imaging modalities. The implant can be in the shape of a brachytherapy spacer or radiotherapy fiducial maker or can be a coating on a brachytherapy spacer or fiducial marker. A method of treating cancer is provided by implanting one or more brachytherapy spacers or fiducial markers including the matrix material and an anti-cancer therapeutic agent dispersed within the matrix material.},
note = {US Patent App. 15/328,711},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{sridhar2016electric,
title = {Electric field encephalography: electric field based brain signal detection and monitoring},
author = {Srinivas Sridhar and Yury Petrov and Ozgur Yavuzcetin},
year = {2016},
date = {2016-03-01},
abstract = {Systems and methods for measuring brain activity of a subject are disclosed, comprising: positioning a plurality of electric field sensors at multiple positions on the exterior of a skull of the subject; measuring one to three components of a plurality of instantaneous electric field vectors generated by a plurality of electric field sources, the electric field vectors being measured by the plurality of electric field sensors; and determining brain activity of the subject based on the measurement of the plurality of instantaneous electric field vectors.},
note = {US Patent App. 14/420,613},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{schuemann2016roadmap,
title = {Roadmap to clinical use of gold nanoparticles for radiation sensitization},
author = {Jan Schuemann and Ross Berbeco and Devika B Chithrani and Sang Hyun Cho and Rajiv Kumar and Stephen J McMahon and Srinivas Sridhar and Sunil Krishnan},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {94},
number = {1},
pages = {189--205},
publisher = {Elsevier},
abstract = {The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{baldwin2016abstract,
title = {Abstract A03: PARP inhibitor nanotherapy for ovarian cancer.},
author = {Paige Baldwin and Anders Ohman and Jeremy Thong and Shifalika Tangutoori and Daniela Dinulescu and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Talazoparib and Olaparib are potent PARP inhibitors that are currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors typically results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (~120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, have been successfully formulated and tested in vitro on several cancer cell lines. KURAMOCHI, SKOV3, and OVSAHO were cultured in RPMI + 10% FBS. JHOS2 was cultured in RPMI + 10% FBS +1% Non-Essential Amino Acids. PA1, COV318, 403, 404, 4412, and 4306 were all cultured in DMEM + 10% FBS. 403 and 404 were derived from tumors of BRCA2-/-¬, PTEN-/-, and TP53mut mice. 4306 and 4412 4306 were developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP mice.
Dose Response: Cell lines were exposed to either Olaparib or NanoOlaparib concentrations ranging from 0 to 100 µM. Each cell line was treated for a total of four doubling cycles to ensure that the percent viability for each cell line was comparable. Cell viability was ascertained with an MTS assay, to measure the metabolic activity of the cells.
Pt synergism: The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from a delayed viability assay.
Results: In vitro studies PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci, each containing (CA)¬n microsatellites. Microsatellite instability has the potential to cause mutations in critical genes that contain coding repeat sequences. This suggests that the genetic instability in PA1 leads to downstream mutations conferring sensitivity to PARP inhibitors.
The murine cell lines, 403, 404 are the next most sensitive group to this treatment due to there triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. Loss of PTEN has been shown to lead to spontaneous DSBs, chromosomal instability, and defects in homologous recombination. While it was expected that cell lines with BRCA1/2 mutations would be some of the most sensitive to these treatments, the results indicate that BRCA mutations and deletions are just as susceptible as PTEN deletions while high genetic instability shows the greatest sensitivity.
NanoTalazoparib is 10-100 times more potent than Olaparib. The cell line dependence is similar to Olaparib except for the overall lower magnitudes.
In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut GEMM also showed good therapeutic response to i.p. administration.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nanotherapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A03.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Three nanoparticle (~120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, have been successfully formulated and tested in vitro on several cancer cell lines. KURAMOCHI, SKOV3, and OVSAHO were cultured in RPMI + 10% FBS. JHOS2 was cultured in RPMI + 10% FBS +1% Non-Essential Amino Acids. PA1, COV318, 403, 404, 4412, and 4306 were all cultured in DMEM + 10% FBS. 403 and 404 were derived from tumors of BRCA2-/-¬, PTEN-/-, and TP53mut mice. 4306 and 4412 4306 were developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP mice.
Dose Response: Cell lines were exposed to either Olaparib or NanoOlaparib concentrations ranging from 0 to 100 µM. Each cell line was treated for a total of four doubling cycles to ensure that the percent viability for each cell line was comparable. Cell viability was ascertained with an MTS assay, to measure the metabolic activity of the cells.
Pt synergism: The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from a delayed viability assay.
Results: In vitro studies PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci, each containing (CA)¬n microsatellites. Microsatellite instability has the potential to cause mutations in critical genes that contain coding repeat sequences. This suggests that the genetic instability in PA1 leads to downstream mutations conferring sensitivity to PARP inhibitors.
The murine cell lines, 403, 404 are the next most sensitive group to this treatment due to there triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. Loss of PTEN has been shown to lead to spontaneous DSBs, chromosomal instability, and defects in homologous recombination. While it was expected that cell lines with BRCA1/2 mutations would be some of the most sensitive to these treatments, the results indicate that BRCA mutations and deletions are just as susceptible as PTEN deletions while high genetic instability shows the greatest sensitivity.
NanoTalazoparib is 10-100 times more potent than Olaparib. The cell line dependence is similar to Olaparib except for the overall lower magnitudes.
In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut GEMM also showed good therapeutic response to i.p. administration.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nanotherapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A03.
©2016 American Association for Cancer Research.@article{markovic2016near,
title = {Near-infrared fluorescence imaging platform for quantifying in vivo nanoparticle diffusion from drug loaded implants},
author = {Stacey Markovic and Jodi Belz and Rajiv Kumar and Robert A Cormack and Srinivas Sridhar and Mark Niedre},
year = {2016},
date = {2016-01-01},
journal = {International journal of nanomedicine},
volume = {11},
pages = {1213},
publisher = {Dove Press},
abstract = {Drug loaded implants are a new, versatile technology platform to deliver a localized payload of drugs for various disease models. One example is the implantable nanoplatform for chemo-radiation therapy where inert brachytherapy spacers are replaced by spacers doped with nanoparticles (NPs) loaded with chemotherapeutics and placed directly at the disease site for long-term localized drug delivery. However, it is difficult to directly validate and optimize the diffusion of these doped NPs in in vivo systems. To better study this drug release and diffusion, we developed a custom macroscopic fluorescence imaging system to visualize and quantify fluorescent NP diffusion from spacers in vivo. To validate the platform, we studied the release of free fluorophores, and 30 nm and 200 nm NPs conjugated with the same fluorophores as a model drug, in agar gel phantoms in vitro and in mice in vivo. Our data verified that the diffusion volume was NP size-dependent in all cases. Our near-infrared imaging system provides a method by which NP diffusion from implantable nanoplatform for chemo-radiation therapy spacers can be systematically optimized (eg, particle size or charge) thereby improving treatment efficacy of the platform.
Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring@article{hau2016dose,
title = {Dose enhancement and cytotoxicity of gold nanoparticles in colon cancer cells when irradiated with kilo-and mega-voltage radiation},
author = {Herman Hau and Dipesh Khanal and Linda Rogers and Natalka Suchowerska and Rajiv Kumar and Srinivas Sridhar and David McKenzie and Wojciech Chrzanowski},
year = {2016},
date = {2016-01-01},
journal = {Bioengineering & translational medicine},
volume = {1},
number = {1},
pages = {94--102},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{sridhar2016sensor,
title = {Sensor system and process for measuring electric activity of the brain, including electric field encephalography},
author = {Srinivas Sridhar and Yury Petrov and Ozgur Yavuzcetin and Kaushik Chowdhury},
year = {2016},
date = {2016-01-01},
abstract = {A sensor system and process for measuring electromagnetic activity of a brain are provided. The system and process employ a sensor assembly having a plurality of electrodes arranged in a closely spaced arrangement and a processor to determine a weighted average of the signals indicative of an electric field generated by electromagnetic activity of the brain. The system provides a medical body area network of a subject including one or more of the sensor assemblies and one or more additional sensors, which may be within a smartphone or other wearable device.},
note = {US Patent App. 14/896,511},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{cormack2016localized,
title = {Localized Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Robert A Cormack and Paul N Nguyen and Anthony V D'Amico and Srinivas Sridhar and Gerassimos Makrigiorgos},
year = {2016},
date = {2016-01-01},
journal = {Brachytherapy},
volume = {15},
pages = {S161--S162},
publisher = {Elsevier},
abstract = {Purpose
In-situ drug release concurrent with radiation therapy may enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.
Methods and Materials
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.
Results
The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.
Conclusions
Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In-situ drug release concurrent with radiation therapy may enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.
Methods and Materials
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.
Results
The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.
Conclusions
Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.@article{belz2016we,
title = {WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer},
author = {J Belz and R Kumar and G Makrigiorgos and A D'Amico and P Nguyen and R Cormack and S Sridhar},
year = {2016},
date = {2016-01-01},
journal = {Medical physics},
volume = {43},
number = {6Part41},
pages = {3823--3823},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{baldwin2016nanoformulations,
title = {Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy},
author = {Paige Baldwin and Anders Ohman and Jeremy Thong and Shifalika Tangutoori and Anne van de Ven and Rajiv Kumar and Daniela Dinulescu and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity. Here we report the development of novel nanoformulations of Olaparib and Talazoparib to allow intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and tested in vitro and in vivo. Short-and long-term dose response with a panel of ovarian cancer cell lines were conducted. These cell lines include KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from BRCA2-/-, PTEN-/-, TP53mut mice, and 4306 and 4412, developed from conditional LSL-K-rasG12D/+, PTENloxP/loxP mice. Radiosensitization with NanoOlaparib was tested in the radiation resistant prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results: The murine cell lines 403 and 404 were highly sensitive to this treatment due to the mutations in BRCA2, PTEN, and TP53. 4412 and 4306 showed comparable sensitivity, suggesting that a PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50’s. Strong synergistic radiosensitization was observed in FK01 cells with NanoOlaparib.
Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib clearly shrinks tumors.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed for in vitro and in vivo studies. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and prostate cancers.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Anne van de Ven, Rajiv Kumar, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4335.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and tested in vitro and in vivo. Short-and long-term dose response with a panel of ovarian cancer cell lines were conducted. These cell lines include KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from BRCA2-/-, PTEN-/-, TP53mut mice, and 4306 and 4412, developed from conditional LSL-K-rasG12D/+, PTENloxP/loxP mice. Radiosensitization with NanoOlaparib was tested in the radiation resistant prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results: The murine cell lines 403 and 404 were highly sensitive to this treatment due to the mutations in BRCA2, PTEN, and TP53. 4412 and 4306 showed comparable sensitivity, suggesting that a PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50’s. Strong synergistic radiosensitization was observed in FK01 cells with NanoOlaparib.
Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib clearly shrinks tumors.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed for in vitro and in vivo studies. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and prostate cancers.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Anne van de Ven, Rajiv Kumar, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4335.
©2016 American Association for Cancer Research.@misc{belz2016sustained,
title = {Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for non-metastatic cancers. Here we report a novel biodegradable implant with the capability to encapsulate therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.
©2016 American Association for Cancer Research.@article{cheng2016endothelial,
title = {Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting},
author = {Ming J Cheng and Rajiv Kumar and Srinivas Sridhar and Thomas J Webster and Eno E Ebong},
year = {2016},
date = {2016-01-01},
journal = {International journal of nanomedicine},
volume = {11},
pages = {3305},
publisher = {Dove Press},
abstract = {Cardiovascular diseases are facilitated by endothelial cell (EC) dysfunction and coincide with EC glycocalyx coat shedding. These diseases may be prevented by delivering medications to affected vascular regions using circulating nanoparticle (NP) drug carriers. The objective of the present study was to observe how the delivery of 10 nm polyethylene glycol-coated gold NPs (PEG-AuNP) to ECs is impacted by glycocalyx structure on the EC surface. Rat fat pad endothelial cells were chosen for their robust glycocalyx, verified by fluorescent immunolabeling of adsorbed albumin and integrated heparan sulfate (HS) chains. Confocal fluorescent imaging revealed a ~3 µm thick glycocalyx layer, covering 75% of the ECs and containing abundant HS. This healthy glycocalyx hindered the uptake of PEG-AuNP as expected because glycocalyx pores are typically 7 nm wide. Additional glycocalyx models tested included: a collapsed glycocalyx obtained by culturing cells in reduced protein media, a degraded glycocalyx obtained by applying heparinase III enzyme to specifically cleave HS, and a recovered glycocalyx obtained by supplementing exogenous HS into the media after enzyme degradation. The collapsed glycocalyx waŝ2 µm thick with unchanged EC coverage and sustained HS content. The degraded glycocalyx showed similar changes in EC thickness and coverage but its HS thickness was reduced to 0.7 µm and spanned only 10% of the original EC surface. Both dysfunctional models retained six- to sevenfold more PEG-AuNP compared to the healthy glycocalyx. The collapsed glycocalyx permitted NPs to cross the glycocalyx into intracellular spaces, whereas the degraded glycocalyx trapped the PEG-AuNP within the glycocalyx. The repaired glycocalyx model partially restored HS thickness to 1.2 µm and 44% coverage of the ECs, but it was able to reverse the NP uptake back to baseline levels. In summary, this study showed that the glycocalyx structure is critical for NP uptake by ECs and may serve as a passive pathway for delivering NPs to dysfunctional ECs.
Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold@article{kunjachan2016po,
title = {PO-0983: Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy},
author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and GM Makrigiorgos and R Berbeco},
year = {2016},
date = {2016-01-01},
journal = {Radiotherapy and Oncology},
volume = {119},
pages = {S477--S478},
publisher = {Elsevier},
abstract = {Purpose or Objective: More than 50% all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation doses is strictly
restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016
_____________________________________________________________________________________________________
Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016
_____________________________________________________________________________________________________
Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.@article{cormack2016situ,
title = {In Situ Radiosensitization of Brachytherapy: Image Guided Planned Biologic Enhancement of Brachytherapy},
author = {RA Cormack and PL Nguyen and AV D'Amico and S Sridhar and M Makrigiorgos},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {E649},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.
Materials/Methods
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).
Results
Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.
Conclusion
Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.
Acknowledgment: DOD PC 110722, Mazzone 2012PD164.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.
Materials/Methods
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).
Results
Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.
Conclusion
Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.
Acknowledgment: DOD PC 110722, Mazzone 2012PD164.@article{baldwin2016nanoformulationb,
title = {Nanoformulation of the PARP inhibitor olaparib enables radiosensitization of a radiation-resistant prostate cancer model},
author = {P Baldwin and AL Van De Ven and N Seitzer and S Clohessy and RA Cormack and M Makrigiorgos and PP Pandolfi and S Sridhar},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {E595},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.
Materials/Methods
Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results
Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.
Conclusion
Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.
Materials/Methods
Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results
Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.
Conclusion
Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.@article{belz2016docetaxel,
title = {Docetaxel-Loaded Brachytherapy Spacers for Combined Chemoradiation Therapy in Prostate Cancer},
author = {J Belz and Castilla N Ojo and R Kumar and RA Cormack and M Makrigiorgos and S Sridhar and AV D'Amico and PL Nguyen},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {S109},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.
Materials/Methods
Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.
Results
The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.
Conclusion
This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.
Materials/Methods
Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.
Results
The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.
Conclusion
This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.@article{kunjachan2016nanoparticle,
title = {Nanoparticle-Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy},
author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and M Makrigiorgos and RI Berbeco},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {S97},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.
Materials/Methods
(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.
Results
RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).
Conclusion
For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.
Materials/Methods
(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.
Results
RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).
Conclusion
For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.@article{reyes2016advancing,
title = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the Treatment of Pancreatic Cancer},
author = {Gino Karlo Lapitan Delos Reyes and Anne Van de Ven and Rasam Soheilian and Srinivas Sridhar and Randall Erb and Hicham Fenniri},
year = {2016},
date = {2016-01-01},
abstract = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the
Treatment of Pancreatic Cancer
Gino Karlo Lapitan Delos Reyes1
, Anne Van de Ven2
, Rasam Soheilian3
, Srinivas Sridhar2
, Randall Erb3
,
Hicham Fenniri2
1
Dept. of Chemical Engineering, 2
Dept. of Physics, 3
Dept. of Mechanical and Industrial Engineering,
Northeastern University, Boston, MA
October 28, 2016
11:45 AM, 105 Shillman Hall
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and
a median survival rate of merely six months following diagnosis1
. State-of-the-art therapies involve
subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side
effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the
cancer phenotype2
. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the
Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)
targeted against the KRAS gene to pancreatic cancer cells and silence the gene.
RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload
to pancreatic cancer cells3
. A defining characteristic and strength of the RNTs as a drug delivery vehicle
is the ability to display various functional groups on their surface during self-assembly, conferring to
them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and
biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness
of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)
and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and
function of using the RNT delivery system.
Methods
In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter
plates according to standard protocols. Groups of cells were then administered the following treatments:
untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are
routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,
functions as a positive control. Post-treatment, the cells were then separated into single cell formations
and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.
Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment
of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the
cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into
replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +
siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The
cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total
mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription
polymerase chain reaction (RT-qPCR).
Results and Discussion
In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated
with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged
siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly
75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using
RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked
siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells
transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS
expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also
comparable to the cells transfected with the Lipofectamine. This result is significant because
Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects
and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective
gene delivery vehicle for the treatment of pancreatic cancer.
Funding Acknowledgements
NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843
NSF CPS-1329649
Northeastern University Chemical Engineering Department
References:
1) P. Michl, T. M. Gress, Gut 2012, 317.
2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.
Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-
7163.MCT-14-0074.
3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.
Am. Chem. Soc. 2001, 123, 3854–3855.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Treatment of Pancreatic Cancer
Gino Karlo Lapitan Delos Reyes1
, Anne Van de Ven2
, Rasam Soheilian3
, Srinivas Sridhar2
, Randall Erb3
,
Hicham Fenniri2
1
Dept. of Chemical Engineering, 2
Dept. of Physics, 3
Dept. of Mechanical and Industrial Engineering,
Northeastern University, Boston, MA
October 28, 2016
11:45 AM, 105 Shillman Hall
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and
a median survival rate of merely six months following diagnosis1
. State-of-the-art therapies involve
subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side
effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the
cancer phenotype2
. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the
Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)
targeted against the KRAS gene to pancreatic cancer cells and silence the gene.
RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload
to pancreatic cancer cells3
. A defining characteristic and strength of the RNTs as a drug delivery vehicle
is the ability to display various functional groups on their surface during self-assembly, conferring to
them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and
biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness
of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)
and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and
function of using the RNT delivery system.
Methods
In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter
plates according to standard protocols. Groups of cells were then administered the following treatments:
untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are
routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,
functions as a positive control. Post-treatment, the cells were then separated into single cell formations
and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.
Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment
of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the
cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into
replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +
siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The
cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total
mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription
polymerase chain reaction (RT-qPCR).
Results and Discussion
In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated
with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged
siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly
75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using
RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked
siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells
transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS
expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also
comparable to the cells transfected with the Lipofectamine. This result is significant because
Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects
and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective
gene delivery vehicle for the treatment of pancreatic cancer.
Funding Acknowledgements
NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843
NSF CPS-1329649
Northeastern University Chemical Engineering Department
References:
1) P. Michl, T. M. Gress, Gut 2012, 317.
2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.
Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-
7163.MCT-14-0074.
3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.
Am. Chem. Soc. 2001, 123, 3854–3855.
@article{van2015essential,
title = {Essential components of a successful doctoral program in nanomedicine},
author = {Anne L van de Ven and Mary H Shann and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International journal of nanomedicine},
volume = {10},
pages = {23},
publisher = {Dove Press},
abstract = {The Nanomedicine program at Northeastern University provides a unique interdisciplinary graduate education that combines experiential research, didactic learning, networking, and outreach. Students are taught how to apply nanoscience and nanotechnology to problems in medicine, translate basic research to the development of marketable products, negotiate ethical and social issues related to nanomedicine, and develop a strong sense of community involvement within a global perspective. Since 2006, the program has recruited 50 doctoral students from ten traditional science, technology, and engineering disciplines to participate in the 2-year specialization program. Each trainee received mentoring from two or more individuals, including faculty members outside the student’s home department and faculty members at other academic institutions, and/or clinicians. Both students and faculty members reported a significant increase in interdisciplinary scholarly activities, including publications, presentations, and funded research proposals, as a direct result of the program. Nearly 90% of students graduating with a specialization in nanomedicine have continued on to careers in the health care sector. Currently, 43% of graduates are performing research or developing products that directly involve nanomedicine. This article identifies some key elements of the Nanomedicine program, describes how they were implemented, and reports on the metrics of success.
Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training@article{kumar2015nanoparticle,
title = {Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jadhav and William Fowle and Mark Niedre and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {91},
number = {2},
pages = {393--400},
publisher = {Elsevier},
abstract = {Purpose
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
@article{tangutoori2015parp,
title = {PARP inhibitors: A new era of targeted therapy},
author = {Shifalika Tangutoori and Paige Baldwin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {Maturitas},
volume = {81},
number = {1},
pages = {5--9},
publisher = {Elsevier},
abstract = {Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cheng2015endothelial,
title = {Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake},
author = {Ming Cheng and Homa Homayoni and Rajiv Kumar and Srinivas Sridhar and Thomas Webster and Eno Ebong},
year = {2015},
date = {2015-01-01},
journal = {The FASEB Journal},
volume = {29},
number = {1_supplement},
pages = {LB168},
publisher = {The Federation of American Societies for Experimental Biology},
abstract = {The endothelial cells in the blood vessels are lined with a meshwork of polysaccharides called the glycocalyx (GCX). There is evidence this protective layer is dysfunctional in patients suffering from various diseases including diabetes, atherosclerosis, and metastatic cancer. GCX dysfunction may impair or amplify the effect of drugs delivered to treat disease, and particularly drugs delivered using nanoparticle vehicles that are becoming very popular. However, there is currently no in vitro process of screening nanoparticle-based drug delivery that tests the role of GCX health in delivery of the nanoparticles or drug itself. To address this issue, we are using ultra-small PEGylated gold nanoparticles (NP) to visualize the effects of GCX on nanoparticle uptake by rat fat pad endothelial cells. We are examining the effect of intact GCX. In addition, two types of GCX dysfunction are modeled: degradation due to the addition of heparinase III enzyme that degrades the heparan sulfate component of the glycocalyx, and collapse due to culturing the cells in low serum media. In another model, we induce GCX regeneration through addition of heparan sulfate after heparinase III treatment. The cells are then incubated with nanoparticles overnight, fixed and stained, then imaged through confocal microscopy. Both cell cultures with damaged GCX showed significantly higher NP uptake compared to the cultures with intact or regenerated GCX. This work indicates that the GCX integrity and composition does influence NP uptake for the endothelial cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cifter2015mo,
title = {MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles},
author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Medical physics},
volume = {42},
number = {6Part29},
pages = {3565--3565},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{adedoyin2015injectable,
title = {Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Restoration of articular hyaline cartilage within osteochondral tissue defects has been a principal target in the field of tissue engineering due to poor functional regeneration of this avascular and heterogeneous tissue following current treatment options. The major focus thus far has been in constructing implantable scaffolds, which can be readily designed to offer appropriate mechanical properties. However, the use of implantable scaffolds requires open surgery and often cannot be readily applied to defects of irregular shape. Thus, it has become of high interest to develop minimally invasive and degradable hydrogel-based materials capable of delivering and maintaining encapsulated cells in a non-toxic manner and encouraging functional tissue regeneration. This paper reports on the synthesis and characterization of a novel class of injectable, thermally and chemically dual-gelling bionanocomposite hydrogels from thermogelling macromers (TGMs) based on poly(N-isopropylacrylamide) (pNiPAAm), degradable polyamidoamine (PAMAMs) crosslinking macromers, and functional hybrid inorganic iron oxide (Fe 3 O 4 ) nanoparticles capable of responding to an external magnetic field to stimulate cell activity and control the regenerative process in situ in a spatiotemporal manner.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{ozturk2015atomically,
title = {Atomically thin layers of B--N--C--O with tunable composition},
author = {Birol Ozturk and Andres de-Luna-Bugallo and Eugen Panaitescu and Ann N Chiaramonti and Fangze Liu and Anthony Vargas and Xueping Jiang and Neerav Kharche and Ozgur Yavuzcetin and Majed Alnaji and others},
year = {2015},
date = {2015-01-01},
urldate = {2015-01-01},
journal = {Science advances},
volume = {1},
number = {6},
pages = {e1500094},
publisher = {American Association for the Advancement of Science},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{kumar2015local,
title = {Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models},
author = {Rajiv Kumar and Jodi Belz and Houari Korideck and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Systemic chemotherapy which is often used in combination with radiation therapy in the treatment of prostate cancer, often leads to severe systemic toxicities. Localized chemotherapy has the potential of delivering a high and effective dose directly to the tumor while minimizing adverse toxicities to healthy tissue. An efficient local delivery system should be able to deliver the therapeutic drug at the diseased site in a slow and sustained manner with minimal systemic toxicity. We have fabricated an Implantable Nanoplatform for Chemo-Radiation Therapy (INCeRT) spacer that can deliver planned, localized, and sustained delivery of a chemotherapeutic and imaging agent. Delivery of this new chemotherapy modality can leverage technology used in a routine clinical brachytherapy procedure that uses image guidance to insert radioactive seeds into the prostate using thin needles. The current procedure uses inert plastic spacers with no therapeutic impact to guide the spatial delivery of the radioactive seeds.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.@misc{tangutoori2015nanoparpi,
title = {NanoPARPi inhibitors for ovarian and prostate cancer therapy},
author = {Shifalika Tangutoori and Paige Bladwin and Anders Ohman and Houari Korideck and Robert Cormack and Daniela Dinulescu and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly ADP Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) or BMN-673 (200μM) and Cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) or BMN-673 (200μM) and Cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.@misc{tangutoori2015abstract,
title = {Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models},
author = {Shifalika Tangutoori and Paige Baldwin and Jamie Medina and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.@article{kunjachan2015nanoparticle,
title = {Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy},
author = {Sijumon Kunjachan and Alexandre Detappe and Rajiv Kumar and Thomas Ireland and Lisa Cameron and Douglas E Biancur and Vincent Motto-Ros and Lucie Sancey and Srinivas Sridhar and Mike G Makrigiorgos and others},
year = {2015},
date = {2015-01-01},
journal = {Nano letters},
volume = {15},
number = {11},
pages = {7488--7496},
publisher = {American Chemical Society},
abstract = {More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{adedoyin2015synthesis,
title = {Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S307--S307},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@inproceedings{cheng2015glycocalyx,
title = {Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells},
author = {MJ Cheng and R Kumar and S Sridhar and TJ Webster and EE Ebong},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S401--S401},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{ozturk2015novel,
title = {A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications},
author = {Birol Ozturk and Ozgur Yavuzcetin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Optics},
volume = {2015},
publisher = {Hindawi},
abstract = {High-aspect-ratio photonic crystal air-hole fabrication on bulk Lithium Niobate (LN) substrates is extremely difficult due to its inherent resistance to etching, resulting in conical structures and high insertion losses. Here, we propose a novel coupled resonator photonic crystal (CRPC) design, combining a coupled resonator approach with that of Bragg gratings. CRPC design parameters were optimized by analytical calculations and FDTD simulations. CRPC structures with optimized parameters were fabricated and electrooptically tested on bulk LN annealed proton exchange waveguides. Low insertion loss and large electrooptic effect were observed with the fabricated devices, making the CRPC design a promising structure for electrooptic device applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{baldwin2015abstract,
title = {Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy},
author = {Paige Baldwin and Ilanchezhian Shanmugam and Shifalika Tangutoori and Anders Ohman and Daniela Dinulescu and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.@misc{belz2015abstract,
title = {Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer},
author = {Jodi Belz and Karen Liby and Paige Baldwin and Rajiv Kumar and Anne L van de Ven and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.@misc{kumar2015abstract,
title = {Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Ilanchezhian Shanmugam and Wilfred Ngwa and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.@misc{tangutoori2015nanoparticle,
title = {Nanoparticle drug delivery system and method of treating cancer and neurotrauma},
author = {Shifalika TANGUTOORI and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
abstract = {The invention provides pharmaceutical formulations of inhibitors for poly (ADP-ribose) polymerase (PARP) enzyme. The formulations can be used in the treatment and prevention of cancer as well as the treatment of neurotrauma and neurodegenerative diseases. The PARP inhibitor is delivered in the form of nanoparticles that provide efficient delivery of the inhibitor into cancer cells or other cells and release of the inhibitor within the cells. In treating cancer, the result is killing of tumor cells, whereas in treatment of neurotrauma and neurodegenerative disease, the result is preservation of cell function.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{clarke2015integrative,
title = {Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer},
author = {Nicole Clarke and Jewison Biscocho and Kevin A Kwei and Jean M Davidson and Sushmita Sridhar and Xue Gong and Jonathan R Pollack},
year = {2015},
date = {2015-01-01},
journal = {PloS one},
volume = {10},
number = {11},
publisher = {Public Library of Science},
abstract = {NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@techreport{debay2015atomically,
title = {Atomically thin layers of BNCO with tuneable composition},
author = {Ann Chiaramonti C Debay and Birol Ozturk and Andres de Luna Bugallo and Eugene Panaitescu and Fangze Liu and Anthony Vargas and Xueping Jiang and Ozgur Yavuzcetin and Majed Alnaji and Yongui Zhao and others},
year = {2015},
date = {2015-01-01},
abstract = {Atomically thin ternary compounds/alloys of boron, nitrogen and carbon have generated significant excitement as they provided the first instance of a tuneable 2D material that affords rich physics as well applications potentials. Interestingly, the crucial role and the possible inclusion of oxygen in the 2D-BNC lattice have never been investigated. Here, we present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon and oxygen, 2D-BNCO. Our experiments suggest and theoretical calculations corroborate stable configurations of a planar honeycomb 2D-BNCO lattice. We observed the growth of micron-scale 2D-BNCO domains within a graphene-rich matrix, and were able to control their area coverage and relative composition by varying the ratio of oxygen content in the growth setup. The introduction of oxygen into the BNC system induces a rich variety of electronic, optical, and magnetic properties.
CitationNano Letters},
keywords = {},
pubstate = {published},
tppubtype = {techreport}
}
CitationNano Letters@inproceedings{teh2015targeting,
title = {Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics},
author = {James Teh and Robert Hanson and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {249},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{wang2015integrity,
title = {Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse},
author = {Haotian Wang and Rajiv Kumar and Dattatri Nagesha and Richard I Duclos Jr and Srinivas Sridhar and Samuel J Gatley},
year = {2015},
date = {2015-01-01},
journal = {Nuclear medicine and biology},
volume = {42},
number = {1},
pages = {65--70},
publisher = {Elsevier},
abstract = {Introduction
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.@article{gharagouzloo2015quantitative,
title = {Quantitative contrast-enhanced MRI with superparamagnetic nanoparticles using ultrashort time-to-echo pulse sequences},
author = {Codi Amir Gharagouzloo and Patrick N McMahon and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {Magnetic resonance in medicine},
volume = {74},
number = {2},
pages = {431--441},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{sinha2015brachytherapy,
title = {Brachytherapy application with in situ dose painting administered by gold nanoparticle eluters},
author = {Neeharika Sinha and Gizem Cifter and Erno Sajo and Rajiv Kumar and Srinivas Sridhar and Paul L Nguyen and Robert A Cormack and Mike G Makrigiorgos and Wilfred Ngwa},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {91},
number = {2},
pages = {385--392},
publisher = {Elsevier},
abstract = {Purpose
Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).
Method and Materials
An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).
Results
Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.
Conclusions
Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS).
Method and Materials
An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131).
Results
Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125.
Conclusions
Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with in situ dose painting administered via gold nanoparticle eluters for prostate cancer.@article{cifter2015next,
title = {Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles: MO-FG-BRA-05},
author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},
year = {2015},
date = {2015-01-01},
journal = {Medical Physics},
volume = {42},
number = {6},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{geilich2015silver,
title = {Silver nanoparticle-embedded polymersome nanocarriers for the treatment of antibiotic-resistant infections},
author = {Benjamin M Geilich and Anne L van de Ven and Gloria L Singleton and Liuda J Sepulveda and Srinivas Sridhar and Thomas J Webster},
year = {2015},
date = {2015-01-01},
journal = {Nanoscale},
volume = {7},
number = {8},
pages = {3511--3519},
publisher = {Royal Society of Chemistry},
abstract = {The rapidly diminishing number of effective antibiotics that can be used to treat infectious diseases and associated complications in a physician's arsenal is having a drastic impact on human health today. This study explored the development and optimization of a polymersome nanocarrier formed from a biodegradable diblock copolymer to overcome bacterial antibiotic resistance. Here, polymersomes were synthesized containing silver nanoparticles embedded in the hydrophobic compartment, and ampicillin in the hydrophilic compartment. Results showed for the first time that these silver nanoparticle-embedded polymersomes (AgPs) inhibited the growth of Escherichia coli transformed with a gene for ampicillin resistance (bla) in a dose-dependent fashion. Free ampicillin, AgPs without ampicillin, and ampicillin polymersomes without silver nanoparticles had no effect on bacterial growth. The relationship between the silver nanoparticles and ampicillin was determined to be synergistic and produced complete growth inhibition at a silver-to-ampicillin ratio of 1 : 0.64. In this manner, this study introduces a novel nanomaterial that can effectively treat problematic, antibiotic-resistant infections in an improved capacity which should be further examined for a wide range of medical applications.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{tangutoori2014we,
title = {WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres},
author = {S Tangutoori and H Korideck and R Kumar and S Sridhar and G Makrigiorgos and R Cormack},
year = {2014},
date = {2014-01-01},
journal = {Medical Physics},
volume = {41},
number = {6Part30},
pages = {518--518},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{petrov2014ultra,
title = {Ultra-dense EEG sampling results in two-fold increase of functional brain information},
author = {Yury Petrov and Jeffrey Nador and Christopher Hughes and Stanley Tran and Ozgur Yavuzcetin and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
journal = {Neuroimage},
volume = {90},
pages = {140--145},
publisher = {Academic Press},
abstract = {We used an ultra-density electroencephalography (ud-EEG) sensor array with improved electrical characteristics to reveal unexpected strong potential variation at 1 cm scale. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for data classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications. Contemporary high-density electroencephalographic systems (hd-EEG) comprising up to 256 electrodes have inter-electrode separations of 2–4 cm. Because electric currents of the brain are believed to strongly diffuse before reaching the scalp surface, higher-density electrode coverage is often deemed unnecessary. We used an ultra-dense electroencephalography (ud-EEG) sensor array to reveal strong potential variation at 1 cm scale and discovered that it reflects functional brain activity. A new classification paradigm demonstrates that ud-EEG provides twice the signal to noise ratio for brain-response classification compared with contemporary hd-EEG. These results suggest a paradigm shift from current thinking by showing that higher spatial resolution sampling of EEG is required and leads to increased functional brain information that is useful for diverse neurological applications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{belz2014localized,
title = {Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants},
author = {Jodi Belz and Rajiv Kumar and Stacey Markovic and Mark Niedre and Srinivas Sridhar and Paul Nguyen and Anthony Damico and Mike Makrigiorgos and Robert Cormack},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Systemic chemotherapy is often used with radiation therapy in the management of prostate cancer, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy replaces inert spacers with no therapeutic impact currently used in brachytherapy, with drug eluting spacers that provide the same spatial benefit with the added localized chemotherapeutic. This new therapeutic modality requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure and compare temporal and spatial properties of diffusion distributions around spacers loaded with multi-sized dye-doped nanoparticles or with free dye. The spacer with optimal diffusive properties was then loaded with chemotherapeutics and inserted intratumorally for efficacy of the local chemotherapy versus the standard systemic dosing.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{sridhar2014361,
title = {361 Nanoformulations of the PARP inhibitors olaparib and BMN 673 for cancer nanotherapy},
author = {S Sridhar and S Tangutoori and P Baldwin},
year = {2014},
date = {2014-01-01},
journal = {European Journal of Cancer},
volume = {50},
pages = {116},
publisher = {Elsevier},
abstract = {Background: Intensive investigations are ongoing to identify and validate predictive molecular markers for anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) and other solid tumour types. However, this proves to be challenging due to multiple resistance mechanisms. Maturing understanding of immuno-oncology functions, including tumour-infiltrating lymphocytes (TIL) and tumour-associated macrophages (TAM), and their influence on mRCC biology provides the opportunity for new insights into sensitivity to anti-angiogenic agents.
Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Materials and Methods: Archival tumour samples were collected on an optional basis and prior to axitinib dosing from 52 patients with mRCC treated with axitinib following 1 prior systemic first-line regimen in the phase III AXIS trial (NCT00678392). Samples were assessed for macrophage (CD68+) and lymphocyte (CD3+) infiltration using immunohistochemistry. Potential associations between these tumourassociated immune cells and clinical efficacy following axitinib treatment were investigated by Kaplan–Meier analysis using median CD68+(0.08 cells/mm2) and CD3+(399.5 cells/mm2) levels as thresholds and by receiver operating characteristics (ROC) analysis. Results: Higher CD68+ levels were associated with longer median progression-free survival (PFS) of 12.0 months for⩾ median CD68+ cells/mm2 vs 3.7 months for< median CD68+ cells/mm2 (hazard ratio= 0.42, log-rank P< 0.01; not subjected to multivariate analysis accounting for clinical variables). Multivariate analysis is ongoing. ROC analysis of PFS at 2, 4, 6, and 8 months generated optimised cut-points for CD68+ cells/mm2; the …@article{berbeco2014targeted,
title = {Targeted gold nanoparticles as vascular disrupting agents during radiation therapy},
author = {RI Berbeco and H Korideck and R Kumar and S Sridhar and A Detappe and W Ngwa and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {90},
number = {1},
pages = {S198},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.
Materials/Methods
We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.
Results
The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.
Conclusions
Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents in conjunction with clinical megavoltage (MV) photon beams. Unlike competing approaches, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for MV irradiation.
Materials/Methods
We have developed and characterized a novel 4th generation gold nanoparticle platform which includes PEGylation for long circulation, Arginylglycylaspartic acid (RGD) for neovascular targeting and AF647 for fluorescence imaging. Theoretical studies were performed using a combination of Monte Carlo and analytical methods. In vitro experiments were performed using a clinical 6 MV photon beam with the HeLa cell line. In vivo imaging experiments were performed in an orthotopic pancreatic cancer model.
Results
The targeted gold nanoparticle platform is non-toxic and stable over six months. TEM imaging demonstrated consistent gold nanoparticle size of 2-3 nm and confocal microscopy showed robust in vitro cell uptake. Theoretical studies predict a 50% dose enhancement to adjacent tumor endothelial cells. Experimental studies in a 6 MV beam found 40-60% damage enhancement with the effect greatest for deeper targets and with the linear accelerator operating in flattening filter free mode. Fluorescence and TEM imaging studies 24 hours post IV injection confirmed (1) preferential uptake in the tumor, (2) low uptake in normal tissue, (3) infiltration of the tumor endothelial cells, and (4) renal clearing of the gold nanoparticles.
Conclusions
Our studies have demonstrated that a substantial therapy enhancement is expected when gold nanoparticles are targeted to tumor endothelial cells prior to clinical radiation therapy. Our concept is compatible with current clinical practice and could offer an important clinical benefit with minimal patient risk.@inproceedings{gharagouzloo2014ute,
title = {UTE angiography with ferumoxytol},
author = {Codi Gharagouzloo and Patrick N McMahon and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Magnetic Resonance Imaging (MRI) is arguably the most clinically pertinent, non-destructive imaging modality for probing deep tissue in the human body. Clinical contrast-enhanced MRI with superparamagnetic iron oxide nanoparticles (SPIONs) is typically performed with T2-weighted imaging. Here we show that ultra-short TE (UTE) imaging with SPIONs produces unambiguous, positive-contrast signals in vivo in mice. Experiments were performed using a SPION containing pharmaceutical, ferumoxytol, in phantoms and in systemic circulation of mice at 7T. 3D UTE angiography was not hampered by susceptibility artifacts or influenced by flow. By negating these effects we were able to produce high SNR and CNR images of the entire vascular system, including the lungs and the heart.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{berbeco201420,
title = {20: Targeted Gold Nanoparticles as Vascular Disrupting Agents during Radiotherapy},
author = {R Berbeco and H Korideck and R Kumar and S Sridhar and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Radiotherapy and Oncology},
volume = {110},
pages = {S10--S11},
publisher = {Elsevier},
abstract = {Results: More than 100 patients with various indications within the broad therapeutic spectrum covered at HIT received one or more post-therapeutic PET/CT measurements. Especially for proton induced activity, we could considerably improve the predictive power of the activity calculation by the refinement of the used crosssections for radionuclide production and, for brain tumour subjects, a refinement of tissue classification based on a novel multi-modal patient model. The initial clinical experience allows identifying the anatomical locations which benefit most from PET-based verification, as well as the shortcomings of the offline data acquisition. Conclusions: Post-therapeutic PET/CT-based treatment verification is fully integrated into the clinical workflow at HIT. Despite the comparatively low signal due to decay and washout during the transfer time distinct to the offline workflow, valuable treatment quality …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{navarro2014phospholipid,
title = {Phospholipid-modified polyethylenimine-based nanopreparations for siRNA--mediated gene silencing: Implications for transfection and the role of lipid components},
author = {Gemma Navarro and Sean Essex and Rupa R Sawant and Swati Biswas and Dattatri Nagesha and Srinivas Sridhar and Conchita Tros de ILarduya and Vladimir P Torchilin},
year = {2014},
date = {2014-01-01},
journal = {Nanomedicine: Nanotechnology, Biology and Medicine},
volume = {10},
number = {2},
pages = {411--419},
publisher = {Elsevier},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{ngwa2014targeted,
title = {Targeted radiotherapy with gold nanoparticles: current status and future perspectives},
author = {Wilfred Ngwa and Rajiv Kumar and Srinivas Sridhar and Houari Korideck and Piotr Zygmanski and Robert A Cormack and Ross Berbeco and Mike G Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Nanomedicine},
volume = {9},
number = {7},
pages = {1063--1082},
publisher = {Future Medicine},
abstract = {Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{faegh2014ultrasensitive,
title = {Ultrasensitive piezoelectric-based microcantilever biosensor: Theory and experiment},
author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
journal = {IEEE/ASME Transactions on Mechatronics},
volume = {20},
number = {1},
pages = {308--312},
publisher = {IEEE},
abstract = {Microcantilever (MC)-based sensors have become an advantageous tool for detection of ultrasmall masses and biological species. Exploiting high affinity of biomolecules, MCs offer a simple, inexpensive, and highly sensitive platform for high throughput diagnosis and analytical sensing. A number of methods have been reported targeting sensitivity enhancement of MC-based systems including geometry modification, employing nanoparticle-enhanced MCs, and operating MCs in lateral and torsional modes. High mode resonating MCs have been reported as a promising sensitivity enhancement method. Although being investigated, there have not been enough analytical high fidelity models describing all dynamics and behavior of MCs operating in high modes with experimental proof. In this study, experimental results of a piezoelectric self-sensing MC operating as a biological sensor at ultrahigh mode along with theoretical verification are presented. Effect of absorbed mass on the frequency shift was investigated using self-sensing and optical measurement methodologies. Mode convergence theory was adopted in order to get the best estimation of resonance frequencies at different modes. Amino groups of aminothenethaiol solution are immobilized over MC. Shift in resonance frequencies in higher modes are measured and the quality factor is calculated proving the fact that sensitivity of MC to detect absorbed masses enhances as the number of modes increases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@incollection{belz2014multifunctional,
title = {Multifunctional nanoparticles in radiation oncology: an emerging paradigm},
author = {Jodi E Belz and Wilfred Ngwa and Houari Korideck and Robert A Cormack and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar and Rajiv Kumar},
year = {2014},
date = {2014-01-01},
booktitle = {The Science and Function of Nanomaterials: From Synthesis to Application},
pages = {75--106},
publisher = {American Chemical Society},
abstract = {The parallel advances in the field of radiation oncology and nanotechnology have created a paradigm changing opportunity to improve the therapeutic outcome in oncology. The integration of nanomedicine in clinical oncology has led to the appreciation of the use of ‘theranostic nanoparticles’ in not only understanding various biological mechanisms associated with cancer, but also in successfully targeting these pathways to modulate the efficacy of treatment. This chapter focuses on the application of various nanoparticle-based formulations to improve radiation therapy. The emphasis is on the functionality of nanoparticles that can modulate the tumor response to radiation, target the molecular pathways, minimize normal tissue toxicities and improve the imaging efficacy for better disease staging and treatment planning. We believe addressing these factors using nanoparticles can shape the future of radiation therapy, facilitating their use towards a personalized medicine approach.},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
@article{sridhar2014wavelet,
title = {Wavelet Transform Techniques for Image Compression-An Evaluation},
author = {S Sridhar and Rajesh P Kumar and KV Ramanaiah},
year = {2014},
date = {2014-01-01},
journal = {International journal of image, graphics and signal processing},
volume = {6},
number = {2},
pages = {54},
publisher = {Modern Education and Computer Science Press},
abstract = {A vital problem in evaluating the picture quality of an image compression system is the difficulty in describing the amount of degradation in reconstructed image, Wavelet transforms are set of mathematical functions that have established their viability in image compression applications owing to the computational simplicity that comes in the form of filter bank implementation. The choice of wavelet family depends on the application and the content of image. Proposed work is carried out by the application of different hand designed wavelet families like Haar, Daubechies, Biorthogonal, Coiflets and Symlets etc on a variety of bench mark images. Selected benchmark images of choice are decomposed twice using appropriate family of wavelets to produce the approximation and detail coefficients. The highly accurate approximation coefficients so produced are further quantized and later Huffman encoded to eliminate the psychovisual and coding redundancies. However the less accurate detailed coefficients are neglected. In this paper the relative merits of different Wavelet transform techniques are evaluated using objective fidelity measures- PSNR and MSE, results obtained provide a basis for application developers to choose the right family of wavelet for image compression matching their application.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{kumar2014smart,
title = {Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Mark Niedre and Wilfred Ngwa and Houari Korideck and Robert Cormack and Paul Nguyen and Anthony D'Amico and Mike Makrigiorgos and others},
year = {2014},
date = {2014-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: We have developed a new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, which involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX and gold nanoparticles). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure providing sustained delivery and drug concentration and with minimal additional inconvenience to the patient. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures.
Methods: We have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed to control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway.
Conclusions: BIS-IGRT is a powerful approach to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Mark Niedre, Wilfred Ngwa, Houari Korideck, Robert Cormack, Paul Nguyen, Anthony D'Amico, Mike Makrigiorgos, Srinivas Sridhar. Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2014-4917
©2014 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Methods: We have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed to control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway.
Conclusions: BIS-IGRT is a powerful approach to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Note: This abstract was not presented at the meeting.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Mark Niedre, Wilfred Ngwa, Houari Korideck, Robert Cormack, Paul Nguyen, Anthony D'Amico, Mike Makrigiorgos, Srinivas Sridhar. Smart brachytherapy spacers eluting nanoencapsulated radiosensitizers for chemo-radiation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2014-4917
©2014 American Association for Cancer Research.@misc{tangutoori2014nanoformulations,
title = {Nanoformulations of PARP inhibtors for cancer therapy},
author = {Shifalika Tangutoori and Paige Baldwin and Houari Korideck and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction:
Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods:
Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays.
Results:
Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway.
Conclusions:
Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397
©2014 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Poly ADP Ribose Polymerase inhibitor therapy (PARPi) exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for oral PARPi in several clinical trials for a variety of cancers. Oral administration in general results in poor bioavailability and tumor accumulation. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN) , thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods:
Two nanoparticle formulations NanoOlaparib and NanoBMN have been successfully formulated and tested in vitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and PARPi nanoformulations defined by ∼163 nm diameter, zeta potential ∼ +10mV, and loaded with olaparib (2.3mM) or BMN-673 (200µM) and cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using MTS assay and EC50's were determined using Prism. The synergism due to radiosensitization using 220 keV beam was studied for both therapies using isobolograms developed from clonogenic assays on prostate and breast cancer cells. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on ovarian cancer cell lines including PA-1, KURAMOCHI etc. The functionality of nanoPARPi/combination formulations on all the cancers, reflected by inhibition of PARylation, γ-H2AX and RAD-51 was determined by immunoflourescence assays.
Results:
Radiosensitization showed strong radiosensitization, achieving long-term cell kill of more than 90% with NanOlaparib and 4 Gy radiation in prostate cancer PC3, VCaP and LNCaP cell lines. VCaP which carries a TMPRSS2: ERG fusion was more responsive than PC3 for monotherapy using NanoOlaparib alone, and had better radiation sensitization compared to the other cell lines tested so far. In all studies NanoOlaparib showed better efficacy in combination with radiation than free Olaparib. Similar studies with nanoBMN are underway.
Conclusions:
Robust nanoparticle formulations NanoOlaparib and NanoOlaparibPt have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN formulations as chemo and radio-sensitizers enabling several therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Baldwin, Houari Korideck, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Nanoformulations of PARP inhibtors for cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2014-2397
©2014 American Association for Cancer Research.@inproceedings{khabiry2014automated,
title = {Automated cell counting method for microgroove based microfluidic device},
author = {Masoud Khabiry and Nader Jalili and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Microfluidic grooves and channels enable the control of cell positioning and capturing of cells in cell-based biosensor applications. Microfluidic devices also provide a platform for cell-based biological assays. Microfluidic channels have been used to capture cells for various cell-based diagnostics and screening applications. The number of cells and cell locations are important factors which will affect the flow pattern in the microfluidic device and consequently induced shear stresses. Moreover, manual cell counting and cell information extraction is a time consuming and tedious task. Automated techniques reduce human errors and expedite the process. Furthermore, it facilitates extraction of information from obtained images for further fluidic analysis.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@inproceedings{van2014polymersomes,
title = {Polymersomes for image-guided therapy},
author = {Anne L van de Ven and Benjamin Geilich and Codi Gharagouzloo and Jacob Barlow and Thomas Webster and Srinivas Sridhar},
year = {2014},
date = {2014-01-01},
booktitle = {2014 40th Annual Northeast Bioengineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Polymersomes are a promising avenue for image-guided therapy of cancer, since they can stably encapsulate a broad range of therapeutic molecules and offer both targeting capacity and stimuli responsiveness. We have formulated highly stable, magnetically activatable polymersomes capable of continuous and pulsed small molecule release. In the proof-of-concept provided here, we demonstrate that these particles are responsive to both external and heat and magnetic fields. At physiologic temperatures, these particles display a sustained release profile that can be reversibly triggered for transient increases in release. The incorporation of fluorescent and iron oxide contrast sources make these particles amenable for quantitative imaging techniques including intravital microscopy (IVM) and ultra-short time-to-echo (UTE) magnetic resonance imaging (MRI). Thus we believe this formulation is uniquely suited for the in vivo study and optimization of externally triggered tumor growth inhibition.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{ngwa2014radiation,
title = {Radiation Therapy Biomaterials for Response Assessment and Nodal Detection (Brand)},
author = {W Ngwa and Y Altundal and H Korideck and R Kumar and S Sridhar and R Cormack and M Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {90},
number = {1},
pages = {S856},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
We propose that routinely used inert radiation therapy (RT) biomaterials (e.g. fiducials, spacers) can be upgraded to smart ones by incorporating multifunctional non-toxic gold nanoparticles (GNPs) for sustained in-situ release. Our hypothesis is that the GNPs released, after implantation of the smart biomaterial in tumor, can be programmed to label/brand metastatic or circulating tumor cells (CTCs) at their source before they are shed into hematogenous or lymphatic circulation. This would enable significantly enhanced CTCs detection by different methods. In this work, we developed and characterized such prototype smart biomaterials. We also assessed the potential for released GNPs to label/brand CTCs over time for enhanced detection by photoacoustic methods.
Materials/Methods
Prototype smart biomaterials were produced by coating inert fiducials with a polymer film loaded with GNPs. In vitro release of GNPs was monitored by UV-Vis Spectroscopy over time. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse prostate tumor model was employed to estimate D for other nanoparticle sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to calculate the diffusion time required to label any CTCs within the tumor volume. CTCs were considered labeled when in contact with an experimentally determined minimum GNPs concentration (37ng/g) detectable by photoacoustic methods. The study was done for a range of tumor sizes and initial concentrations.
Results
Our prototype smart biomaterial showed sustained customizable release of GNP in vitro, with release profile reaching steady state after 2 hours. Meanwhile, for the experimentally determined D, results using an initial concentration of 7 mg/g showed it would take 7.6-17.3 days for the released GNP to brand any CTCs located within the tumor volume of diameter 2-3 cm. The labeling time decreased with decrease in GNP size or increase in initial concentration.
Conclusions
Considered together, our results demonstrate potential for labeling CTCs right from the source tumor, with the labeling customizable through nanoparticle design: size, initial concentration, etc. The highest clinical impact of this innovative approach is anticipated in significantly enhancing the isolation and detection efficiency of CTCs in circulation or lymph nodes towards improved characterization of tumor aggressiveness, treatment response, or prognosis. The ability to brand and track CTCs right from their source could also lead to a better understanding of mechanisms contributing to cancer progression or metastasis. The innovative approach would come at no additional inconvenience to RT patients who are candidates for the currently used inert RT biomaterials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We propose that routinely used inert radiation therapy (RT) biomaterials (e.g. fiducials, spacers) can be upgraded to smart ones by incorporating multifunctional non-toxic gold nanoparticles (GNPs) for sustained in-situ release. Our hypothesis is that the GNPs released, after implantation of the smart biomaterial in tumor, can be programmed to label/brand metastatic or circulating tumor cells (CTCs) at their source before they are shed into hematogenous or lymphatic circulation. This would enable significantly enhanced CTCs detection by different methods. In this work, we developed and characterized such prototype smart biomaterials. We also assessed the potential for released GNPs to label/brand CTCs over time for enhanced detection by photoacoustic methods.
Materials/Methods
Prototype smart biomaterials were produced by coating inert fiducials with a polymer film loaded with GNPs. In vitro release of GNPs was monitored by UV-Vis Spectroscopy over time. An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse prostate tumor model was employed to estimate D for other nanoparticle sizes using the Stoke-Einstein equation. The error function diffusion model in the experimental study was applied to calculate the diffusion time required to label any CTCs within the tumor volume. CTCs were considered labeled when in contact with an experimentally determined minimum GNPs concentration (37ng/g) detectable by photoacoustic methods. The study was done for a range of tumor sizes and initial concentrations.
Results
Our prototype smart biomaterial showed sustained customizable release of GNP in vitro, with release profile reaching steady state after 2 hours. Meanwhile, for the experimentally determined D, results using an initial concentration of 7 mg/g showed it would take 7.6-17.3 days for the released GNP to brand any CTCs located within the tumor volume of diameter 2-3 cm. The labeling time decreased with decrease in GNP size or increase in initial concentration.
Conclusions
Considered together, our results demonstrate potential for labeling CTCs right from the source tumor, with the labeling customizable through nanoparticle design: size, initial concentration, etc. The highest clinical impact of this innovative approach is anticipated in significantly enhancing the isolation and detection efficiency of CTCs in circulation or lymph nodes towards improved characterization of tumor aggressiveness, treatment response, or prognosis. The ability to brand and track CTCs right from their source could also lead to a better understanding of mechanisms contributing to cancer progression or metastasis. The innovative approach would come at no additional inconvenience to RT patients who are candidates for the currently used inert RT biomaterials.@article{cormack2014f,
title = {SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy},
author = {R Cormack and W Ngwa and S Tangutoori and K Rajiv and S Sridhar and G Makrigiorgos},
year = {2014},
date = {2014-01-01},
journal = {Medical Physics},
volume = {41},
number = {6Part22},
pages = {389--390},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{petrovelectric,
title = {Electric Field Encephalography: Electric fields and their application to functional brain imaging.},
author = {Yury Petrov and Srinivas Sridhar},
year = {2013},
date = {2013-07-03},
abstract = {We introduce the notion of Electric Field Encephalography (EFEG) based on measuring electric fields of the brain and demonstrate, using computer modeling, that given the appropriate electric field sensors this technique may have significant advantages over the current EEG technique. Unlike EEG, EFEG can be used to measure brain activity in a contactless and reference-free manner at significant distances from the head surface. Principal component analysis using simulated cortical sources demonstrated that electric field sensors positioned 3 cm away from the scalp and characterized by the same signal-to-noise ratio as EEG sensors provided the same number of uncorrelated signals as scalp EEG. When positioned on the scalp, EFEG sensors provided 2–3 times more uncorrelated signals. This significant increase in the number of uncorrelated signals can be used for more accurate assessment of brain states for non-invasive brain-computer interfaces and neurofeedback applications. It also may lead to major improvements in source localization precision
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{yavuzcetin2013fabrication,
title = {Fabrication and characterization of single mode annealed proton exchanged waveguides in-x-cut lithium niobate},
author = {O Yavuzcetin and Nicholas R Perry and Sean T Malley and Rebecca L Dally and Herman P Novikov and Birol Ozturk and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Optical Materials},
volume = {36},
number = {2},
pages = {372--375},
publisher = {North-Holland},
abstract = {Lithium niobate is a key, well-known material in optical communication that maintains its importance due to its high speed in electro-optical modulators and other optical devices. Using a benzoic acid proton exchange method and annealing in wet O2, we have fabricated waveguides along the y-axis of -x-cut lithium niobate substrate. We have optimized proton exchange and annealing time to make waveguides with the highest transmission we observed to date. The optical transmission was measured in waveguides between 3 μm and 7 μm in width, and 10 mm in length. The near-field mode properties of the waveguides were also examined. In addition, we discovered that the transmission through waveguides is reduced by the surface residues which are underestimated in most fabrication processes. This paper outlines the full fabrication process as well as characterization methods in detail, including a supercontinuum laser source.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{gharagouzloo2013ultrashort,
title = {Ultrashort TE imaging with SPIONs: bright prospects for in vivo applications},
author = {CA Gharagouzloo and S Madi and RT Seethamraju and M Harisinghani and S Sridhar},
year = {2013},
date = {2013-01-01},
booktitle = {JOURNAL OF NUCLEAR MEDICINE},
volume = {54},
pages = {9--9},
organization = {SOC NUCLEAR MEDICINE INC 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@misc{gharagouzloo2013positive,
title = {Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery.},
author = {Codi Gharagouzloo and Manasa Jillela and Rajiv Kumar and Dattatri Nagesha and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {During the last 2 decades no new clinical MRI agents have been approved for clinical use. While Gadolinium based agents have been very popular, Gd cannot be used in emerging multi-functional nano platforms that have the potential to be retained in the body leading to severe toxicity. Superparamagnetic iron-oxide nanoparticles (SPIONs) are most attractive as offering a significant alternative that is far less toxic than Gd based agents. They can be incorporated into nanoplatforms combining other therapeutic agents to achieve image guided drug delivery. Conventionally, SPIONs are imaged via T2 and T2* weighted techniques which manifest signal voids for SPION-containing media. This proves to be disadvantageous in most circumstances because of the difficulty in discriminating signal loss from tissue associated partial voluming, perivascular effects, susceptibility artifacts and motion or flow artifacts. The unique combination of SPIONs with ultra-short TE (UTE) imaging has the specific advantages of rendering positive contrast with high SNR and high CNR, since non-SPION containing regions are dramatically dark due to native tissue's comparatively higher T1. With UTE, it may be possible to take advantage of SPION's inherent biocompatibility allowing for incorporation into drug loaded nanoplatforms leading to bright contrast and the possibility of in vivo quantification.
Here, we report on a systematic study of positive contrast MR imaging using magnetic nanoplatforms incorporating SPIONs of varying particle size and functionalization. In the first step, nanoparticles of various sizes from 4 nm to 20 nm were synthesized by the thermal decomposition method in organic solvents and then coated with phospholipids containing PEG. The use of PEGylated phospholipid enables water solubility, imparts better dispersity and long circulation in blood stream. This results in a core-shell like morphology with iron oxide nanoparticle forming the core and phospholipid PEG forming the shell. The nanoparticles were characterized for their size and morphology using dynamic light scattering (DLS) and transmission electron microscopy (TEM). UTE was optimized on a Bruker 7T Biospec at the Center for Translational Neuroimaging (CTNI) at Northeastern University. High-contrast images were obtained by modification of various imaging parameters such as TE, TR, flip angle, pulse length, polar under-sampling, bandwidth and FOV/Geometry. The results are compared in vivo with Feraheme and show good promise for this approach to MR nanoparticle imaging.
We acknowledge partial support from NSF DGE 0965843, HHS/5U54CA151881-02, and the Electronics Materials Research Institute at Northeastern University.
Citation Format: Codi Gharagouzloo, Manasa Jillela, Rajiv Kumar, Dattatri Nagesha, Srinivas Sridhar. Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2673. doi:10.1158/1538-7445.AM2013-2673
©2013 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Here, we report on a systematic study of positive contrast MR imaging using magnetic nanoplatforms incorporating SPIONs of varying particle size and functionalization. In the first step, nanoparticles of various sizes from 4 nm to 20 nm were synthesized by the thermal decomposition method in organic solvents and then coated with phospholipids containing PEG. The use of PEGylated phospholipid enables water solubility, imparts better dispersity and long circulation in blood stream. This results in a core-shell like morphology with iron oxide nanoparticle forming the core and phospholipid PEG forming the shell. The nanoparticles were characterized for their size and morphology using dynamic light scattering (DLS) and transmission electron microscopy (TEM). UTE was optimized on a Bruker 7T Biospec at the Center for Translational Neuroimaging (CTNI) at Northeastern University. High-contrast images were obtained by modification of various imaging parameters such as TE, TR, flip angle, pulse length, polar under-sampling, bandwidth and FOV/Geometry. The results are compared in vivo with Feraheme and show good promise for this approach to MR nanoparticle imaging.
We acknowledge partial support from NSF DGE 0965843, HHS/5U54CA151881-02, and the Electronics Materials Research Institute at Northeastern University.
Citation Format: Codi Gharagouzloo, Manasa Jillela, Rajiv Kumar, Dattatri Nagesha, Srinivas Sridhar. Positive contrast imaging of magnetic nanoplatforms for image-guided drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2673. doi:10.1158/1538-7445.AM2013-2673
©2013 American Association for Cancer Research@article{ngwa2013vitro,
title = {In vitro radiosensitization by gold nanoparticles during continuous low-dose-rate gamma irradiation with I-125 brachytherapy seeds},
author = {Wilfred Ngwa and Houari Korideck and Amin I Kassis and Rajiv Kumar and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2013},
date = {2013-01-01},
journal = {Nanomedicine: Nanotechnology, Biology and Medicine},
volume = {9},
number = {1},
pages = {25--27},
publisher = {Elsevier},
abstract = {This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources.
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5 cGy/h. Residual γH2AX was measured 24 h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70%–130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
This communication reports the first experimental evidence of gold nanoparticle (AuNP) radiosensitization during continuous low-dose-rate (LDR) gamma irradiation with low-energy brachytherapy sources. HeLa cell cultures incubated with and without AuNP were irradiated with an I-125 seed plaque designed to produce a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at low-dose rates ranging from 2.1 to 4.5 cGy/h. Residual γH2AX was measured 24 h after irradiation and used to compare radiation damage to the cells with and without AuNP. The data demonstrate that the biological effect when irradiating in the presence of 0.2 mg/ml concentration of AuNP is about 70%–130% greater than without AuNP. Meanwhile, without radiation, the AuNP showed minimal effect on the cancer cells. These findings provide in vitro evidence that AuNP may be employed as radiosensitizers during continuous LDR brachytherapy.
@article{rivera2013fibronectin,
title = {Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces},
author = {DM Rivera-Chacon and M Alvarado-Velez and CY Acevedo-Morantes and SP Singh and E Gultepe and D Nagesha and S Sridhar and JE Ramirez-Vick},
year = {2013},
date = {2013-01-01},
journal = {Journal of biomedical nanotechnology},
volume = {9},
number = {6},
pages = {1092--1097},
publisher = {American Scientific Publishers},
abstract = {We studied the influence of the serum proteins fibronectin (FN) and vitronectin (VN) with nanoporous TiO2 on osteoblast cell attachment. Taken together, these results suggest that the nanoporous surface topography results in increased adsorbtion of FN and VN the slow release of these proteins are important factors in osteoblast attachment to titanium alloys.
Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6Al4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6Al4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Improvements in osteoconduction of implant biomaterials require focusing on the bone-implant interface, which is a complex multifactorial system. Surface topography of implants plays a crucial role at this interface. Nanostructured surfaces have been shown to promote serum protein adsorption and osteoblast adhesion when compared to micro-structured surfaces for bone-implant materials. We studied the influence of the serum proteins fibronectin and vitronectin on the attachment and proliferation of osteoblasts onto nanostructured titania surfaces. Human fetal osteoblastic cells hFOB 1.19 were used as model osteoblasts and were grown on nanoporous TiO2 templates, using Ti6Al4V and commercially pure Ti substrates as controls. Results show a significant increase in cell proliferation on nanoporous TiO2 over flat substrates. Initial cell attachment data exhibited a significant effect by either fibronectin or vitronectin on cell adhesion at the surface of any of the tested materials. In addition, the extent of cell adhesion was significantly different between the nanoporous TiO2 and both Ti6Al4V and commercially pure Ti substrates, with the first showing the highest surface coverage. There was no significant difference on osteoblast attachment or proliferation between the presence of fibronectin or vitronectin using any of the material substrates. Taken together, these results suggest that the increase in osteoblast attachment and proliferation shown on the nanoporous TiO2 is due to an increase in the adsorption of fibronectin and vitronectin because of the higher surface area and to an enhanced protein unfolding, which allows access to osteoblast binding motifs within these proteins.@article{faegh2013self,
title = {A self-sensing piezoelectric microcantilever biosensor for detection of ultrasmall adsorbed masses: theory and experiments},
author = {Samira Faegh and Nader Jalili and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
urldate = {2013-01-01},
journal = {Sensors},
volume = {13},
number = {5},
pages = {6089--6108},
publisher = {Multidisciplinary Digital Publishing Institute},
abstract = {Detection of ultrasmall masses such as proteins and pathogens has been made possible as a result of advancements in nanotechnology. Development of label-free and highly sensitive biosensors has enabled the transduction of molecular recognition into detectable physical quantities. Microcantilever (MC)-based systems have played a widespread role in developing such biosensors. One of the most important drawbacks of all of the available biosensors is that they all come at a very high cost. Moreover, there are certain limitations in the measurement equipments attached to the biosensors which are mostly optical measurement systems. A unique self-sensing detection technique is proposed in this paper in order to address most of the limitations of the current measurement systems. A self-sensing bridge is used to excite piezoelectric MC-based sensor functioning in dynamic mode, which simultaneously measures the system’s response through the self-induced voltage generated in the piezoelectric material. As a result, the need for bulky, expensive read-out equipment is eliminated. A comprehensive mathematical model is presented for the proposed self-sensing detection platform using distributed-parameters system modeling. An adaptation strategy is then implemented in the second part in order to compensate for the time-variation of piezoelectric properties which dynamically improves the behavior of the system. Finally, results are reported from an extensive experimental investigation carried out to prove the capability of the proposed platform. Experimental results verified the proposed mathematical modeling presented in the first part of the study with accuracy of 97.48%. Implementing the adaptation strategy increased the accuracy to 99.82%. These results proved the measurement capability of the proposed self-sensing strategy. It enables development of a cost-effective, sensitive and miniaturized mass sensing platform.
Keywords: microcantilever; biosensor; distributed-parameter modeling; mass detection},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Keywords: microcantilever; biosensor; distributed-parameter modeling; mass detection@article{chapman2013nanoparticles,
title = {Nanoparticles for cancer imaging: The good, the bad, and the promise},
author = {Sandra Chapman and Marina Dobrovolskaia and Keyvan Farahani and Andrew Goodwin and Amit Joshi and Hakho Lee and Thomas Meade and Martin Pomper and Krzysztof Ptak and Jianghong Rao and others},
year = {2013},
date = {2013-01-01},
journal = {Nano today},
volume = {8},
number = {5},
pages = {454--460},
publisher = {Elsevier},
abstract = {Recent advances in molecular imaging and nanotechnology are providing new opportunities for biomedical imaging with great promise for the development of novel imaging agents. The unique optical, magnetic, and chemical properties of materials at the scale of nanometers allow the creation of imaging probes with better contrast enhancement, increased sensitivity, controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal imaging across MRI, PET, SPECT, and ultrasound. These features could ultimately translate to clinical advantages such as earlier detection, real time assessment of disease progression and personalized medicine. However, several years of investigation into the application of these materials to cancer research has revealed challenges that have delayed the successful application of these agents to the field of biomedical imaging. Understanding these challenges is critical to take full advantage of the benefits offered by nano-sized imaging agents. Therefore, this article presents the lessons learned and challenges encountered by a group of leading researchers in this field, and suggests ways forward to develop nanoparticle probes for cancer imaging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{kumar2013third,
title = {Third generation gold nanoplatform optimized for radiation therapy},
author = {Rajiv Kumar and Houari Korideck and Wilfred Ngwa and Ross I Berbeco and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Translational cancer research},
volume = {2},
number = {4},
publisher = {NIH Public Access},
abstract = {We report the design and fabrication of third generation ultrasmall PEGylated gold nanoparticles based platform (AuRad™) optimized for applications in radiation therapy. The AuRad™ nanoplatform has the following key features: (I) surface coating of hetero-bifunctional-PEG with amine, carboxyl, methoxy functional groups, which make this a versatile nanoplatform to conjugate various moieties like fluorophores, peptides, drugs, radiolabels; (II) size that is optimized for longer circulation, higher tumor uptake and modulated clearance; (III) high radiation enhancement. We have synthesized ultrasmall 2–3 nm gold nanoparticles, followed by attachment of hetero-bifunctional PEG and further conjugation of fluorophore AlexaFlour 647 for optical imaging, with a stability of more than 6 months. Confocal bioimaging with HeLa cells showed robust uptake of biocompatible nanoparticles in cells. Irradiation experiments X-rays showed greater than 2.8-fold cell kill enhancement as demonstrated by clonogenic survival assays. The results indicate that AuRad nanoplatform can act as potential theranostic agent in radiation therapy.
Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Keywords: Gold nanoparticles, PEGylation, multifunctional nanoparticles, clonogenic assay, radiation therapy@article{petrov2013electric,
title = {Electric field encephalography as a tool for functional brain research: a modeling study},
author = {Yury Petrov and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {PloS one},
volume = {8},
number = {7},
publisher = {Public Library of Science},
abstract = {We introduce the notion of Electric Field Encephalography (EFEG) based on measuring electric fields of the brain and demonstrate, using computer modeling, that given the appropriate electric field sensors this technique may have significant advantages over the current EEG technique. Unlike EEG, EFEG can be used to measure brain activity in a contactless and reference-free manner at significant distances from the head surface. Principal component analysis using simulated cortical sources demonstrated that electric field sensors positioned 3 cm away from the scalp and characterized by the same signal-to-noise ratio as EEG sensors provided the same number of uncorrelated signals as scalp EEG. When positioned on the scalp, EFEG sensors provided 2–3 times more uncorrelated signals. This significant increase in the number of uncorrelated signals can be used for more accurate assessment of brain states for non-invasive brain-computer interfaces and neurofeedback applications. It also may lead to major improvements in source localization precision. Source localization simulations for the spherical and Boundary Element Method (BEM) head models demonstrated that the localization errors are reduced two-fold when using electric fields instead of electric potentials. We have identified several techniques that could be adapted for the measurement of the electric field vector required for EFEG and anticipate that this study will stimulate new experimental approaches to utilize this new tool for functional brain research.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{faegh2013cost,
title = {A cost-effective self-sensing biosensor for detection of biological species at ultralow concentrations},
author = {Samira Faegh and Nader Jalili and Ozgur Yavuzcetin and Dattatri Nagesha and Rajiv Kumar and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Journal of Applied Physics},
volume = {113},
number = {22},
pages = {224905},
publisher = {American Institute of Physics},
abstract = {Detection of ultrasmall masses and identification of biological molecules have been made possible as a result of advances in nanotechnology. Development of biosensing tools has significantly contributed to high-throughput diagnosis and analytical sensing exploiting high affinity of biomolecules. MicroCantilever (MC)-based detection has emerged as a promising biosensing tool for offering label-free and cost-effective sensing capabilities. One of the main criteria determining the success of each biosensor is the capability of the sensing platform to operate in aqueous media. Although being characterized with high sensitivity and simplicity, MCs do not provide an effective tool for measurement of marker proteins in liquid media due to large hydrodynamic damping and losses in the surrounding liquid. In this study, we describe two approaches to high sensitivity biomolecular detection using piezoelectric microcantilevers. (i) Immobilized Mass Detection in Air using electro-mechanical resonance: a unique self-sensing measurement technique is reported utilizing a self-sensing circuit consisting of a piezoelectric MC to address the mentioned limitation. The capability of the self-sensing measurement technique was first verified by detecting ultrasmall biological masses immobilized over the surface of MC by monitoring the shift in fundamental mechanical resonance frequency of the system in air and comparing it with optical-based measurement. This was further utilized for calibration of mass detection in liquid media. (ii) Immobilized Mass Detection in Liquid using the electrical self-sensing circuit's resonance: Once the capability to detect adsorbed mass was verified, the self-sensing platform was implemented to detect different concentrations of target molecule (glucose in this study) in liquid media by adopting the highly sensitive resonance frequency of the whole circuit instead of the mechanical response of MC. Molecular binding occurring over the surface of MC changes the capacitance of the total interface thus changing the resonance frequency of the circuit. The amount of shift in the measured circuit's resonance frequency provides qualitative and quantitative insight into the amount of target protein concentration. The reported diagnostic platform offers a simple, cost-effective, all-electronics method of detection where the need for any bulky, expensive optical based measurement is eliminated. Utilizing this technique, physiological concentration of glucose as low as 500 nM was measured in liquid media. This sensitivity is significantly higher than what has been previously reported using other mechanical resonance techniques.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{ngwa2013toward,
title = {Toward Customizable Radiation Therapy Enhancement (CuRE) With Gold Nanoparticles Released, In Situ, From Gold-Loaded Brachytherapy Spacers},
author = {W Ngwa and H Korideck and R Kumar and S Sridhar and K David and N Paul and R Berbeco and R Cormack and G Makrigiorgos},
year = {2013},
date = {2013-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {87},
number = {2},
pages = {S151},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.
Materials/Methods
Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.
Results
Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.
Conclusions
The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Loading routinely used brachytherapy spacers with non-toxic/biocompatible gold nanoparticles (AuNP), which can be released in situ to serve as radiosensitizers is a novel potential strategy for prostate tumor sub-volume boosting or dose-painting. This study investigates the release and diffusion of the AuNP from the brachytherapy spacer in vivo using CT imaging.
Materials/Methods
Gold-loaded brachytherapy spacers (GBS) (ca. 0.8 mm x 5 mm) were produced using AuNP and biodegradable PLGA copolymer. The GBS was implanted in mice using a brachytherapy needle and CBCT-imaged over time using the small animal radiation research platform (SARRP). The CT images were exported to imageJ and the intensity of the implanted spacer evaluated at different time points. Also, to simulate a burst release of the AuNP from an implanted spacer, 20 mg Au/mL concentration of 15 nm polymer coated AuNP suspended in 20 μL phosphate-buffered saline at pH 7.4, was injected intratumorally, and the AuNP diffusion monitored via serial CT imaging over 5 time points in hours: 0.5, 48, 120, 144, and 160. The CT images were then exported to imageJ and the pixel intensities for 5 sample tumor regions of interest (at: left, right, center, anterior, posterior) extracted to assess AuNP diffusion.
Results
Results for the implanted GBS showed that the CT intensity of the spacer decreased over time, indicating the release of the AuNP as the PLGA degrades in vivo. Meanwhile, the CBCT images from the AuNP burst release study showed clear evidence of AuNP diffusion. For example, at the site of AuNP release, the CT image intensity decreased by over 160% during the investigated time range (0.5 h – 160 h). During the same time, the intensity in the tumor subvolume or ROI on the opposite side of the release site increased by over 140%. The diffusion results also showed that for the 15 nm AuNP size, potent AuNP concentrations can reside within the tumor sub-volume for a sustained period of time.
Conclusions
The results provide the first in vivo evidence of AuNP release from gold loaded brachytherapy spacers. The sustained residence of potent AuNP concentrations in the tumor sub-volume could allow for significant dose boosting during brachytherapy. Such boosting could be further customized (e.g., by varying AuNP size, functionalization, spacer degradation time, etc.) since the intra-tumor biodistribution depends on such parameters. Overall, the results provide a useful basis for future R&D towards the development of Customizable Radiation therapy Enhancement (CuRE) with AuNP for prostate cancer. Potential clinical applications for such a new approach are anticipated in salvage brachytherapy, and sub-volume radiation boosting during initial treatment to help prevent prostate cancer recurrence.@misc{tangutoori2013abstract,
title = {Abstract A81: A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer.},
author = {Shifalika Tangutoori and Houari Korideck and Mike Makrigiorgos and Robert Cormack and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{kumar2013facile,
title = {Facile synthesis of PEGylated PLGA nanoparticles encapsulating doxorubicin and its in vitro evaluation as potent drug delivery vehicle},
author = {Rajiv Kumar and Apurva Kulkarni and Jude Nabulsi and Dattatri K Nagesha and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
journal = {Drug delivery and translational research},
volume = {3},
number = {4},
pages = {299--308},
publisher = {Springer US},
abstract = {The advent of nanotechnology has bolstered a variety of nanoparticle-based platforms for different biomedical applications. A better understanding for engineering novel nanoparticles for applications in cancer staging and therapy requires careful assessment of the nanoparticle’s physico-chemical properties. Herein we report a facile synthesis method for PEGylated PLGA nanoparticles encapsulating anti-cancer drug doxorubicin for cancer imaging and therapy. The simple nanoprecipitation method reported here resulted in very robust PEGylated PLGA nanoparticles with close to 95 % drug encapsulation efficiency. The nanoparticles showed a size of ~110 nm as characterized by TEM and DLS. The nanoparticles were further characterized by optical UV–Visible and fluorescence spectroscopy. The encapsulated doxorubicin showed a sustained release (>80 %) from the nanoparticles matrix over a period of 8 days. The drug delivery efficiency of the nanoparticles was confirmed in vitro confocal imaging with PC3 and HeLa cell lines. In vitro quantitative estimation of drug accumulation in PC3 cell line showed a 22 times higher concentration of drug in case of nanoparticle-based formulation in comparison to free drug and this was further reflected in the in vitro cytotoxicity assays. Overall the synthesis method reported here provides a simple and robust PLGA-based platform for efficient drug delivery and imaging of cancer cells in vitro and in vivo.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{teh2013synthesis,
title = {Synthesis and characterization of Arg-Gly-Asp (RGD) peptidomimetics functionalized onto gold nanoparticles},
author = {James L Teh and Robert N Hanson and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {245},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@misc{kumar2013sustained,
title = {Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy.},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jadhav and Paul Nguyen and Mark Niedre and Anthony DAmico and Mike Makrigiorgos and Robert Cormack and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {Systemic chemotherapy is often used with radiation therapy in the management of prostate, cervix and lung cancer patients, but leads to severe systemic toxicities. We have introduced a new modality of loco-regional chemoradiation therapy termed in-situ image guided radiation therapy (BIS-IGRT) that offers the potential to deliver planned, localized and sustained delivery of chemotherapy agent, without systemic toxicities, as part of routine minimally invasive image guided radiation therapy procedures. Such image guided chemoradiation therapy requires characterization of the drug distribution produced by implantable drug eluters. This work presents imaging based means to measure temporal and spatial properties of diffusion distributions around spacers coated with dye-loaded nanoparticles.
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with >1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2013-1594
©2013 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
The distribution of 250nm silica nanoparticles (NP) conjugated to Cyanine 7.5 dye was evaluated with a custom built high-speed near-infrared small animal imaging platform providing 0.1 millimeter spatial resolution with >1Hz image acquisition rate. A brachytherapy spacer loaded with the Cy7.5/silica NP was injected subcutaneously on the left hind flank of a mouse and one was inserted into a xenograft tumor on the opposite flank as part of an approved animal research protocol. The mouse was imaged more than 36 days.
The in vivo imaging experiments show that the area of high signal increases with time suggesting that NP accumulate in the vicinity of a spacer without diffusing to the rest of the body. The spatial and temporal characteristics of NP accumulation indicate that a BIS-IGRT approach may provide an effective means to improve the therapeutic ratio of brachytherapy.
Conclusion: In-vivo measurements demonstrate that NP remain resident in the vicinity of the implanted eluting spacers with accumulation over times appropriate to improve brachytherapy's therapeutic ratio. Future work will optimize the NP and substrate properties of an implantable spacer to attain the optimal chemotherapy distributions for simultaneous placement during image guided brachytherapy implants.
We acknowledge partial support from NSF DGE 0965843 and HHS/5U54CA151881-02.
Citation Format: Rajiv Kumar, Jodi Belz, Stacey Markovic, Tej Jadhav, Paul Nguyen, Mark Niedre, Anthony DAmico, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. Sustained release of drug eluting nanoparticles from implantable devices for loco-regional chemoradiation therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2013-1594
©2013 American Association for Cancer Research@misc{kumar2013abstract,
title = {Abstract A82: Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’implants.},
author = {Rajiv Kumar and Jodi E Belz and Stacey Markovic and Houari Korideck and Wilfred F Ngwa and Mark Niedre and Ross I Berbeco and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
publisher = {American Association for Cancer Research},
abstract = {In cancer therapy, effective delivery of the therapeutic plays a critical role in determining the success of the treatment planning system. In last decade, there is a major thrust in developing novel nanoparticles based delivery systems to improve the therapeutic benefits in cancer. An efficient delivery system should be able to target the diseased site with minimal systemic toxicity and a slow sustained release of the drug. Here, we have fabricated a nanoparticles based smart ‘INCeRT’ (Implantable Nanoplatform for Chemo-Radiation Therapy) implant for localized delivery of radiosensitizing nanoparticles/ drugs in prostate cancer in conjunction with brachytherapy. These implants are physically similar to the clinically used brachytherapy spacers but have the added capability of imaging and local drug delivery. We have fabricated INCeRT spacers with biocompatible and biodegradable polymer, PLGA (poly-(lactide-co-glycolide)) impregnated with nanoparticles encapsulating imaging probe (Cyanine 7.5) and chemotherapeutic drug, docetaxel (DTX). Using a similar approach, we have also fabricated PLGA spacers impregnated with high Z (atomic number) gold nanoparticles (Hi-Z-CuRE: High Z-Customizable Radiotherapy Enhancement) for effectively boosting the radiation dose locally. The morphology, composition and nanoparticle's distribution inside the spacers was studied by SEM (scanning electron microscopy) and EDS (Energy-dispersive X-ray spectroscopy). Further, preliminary in vivo imaging experiments with subcutaneous prostate cancer tumored mice implanted with INCeRT spacers showed a size dependent diffusion of nanoparticles from the spacers in the tumor matrix. Also, from in vivo therapeutic studies with these spacers showed a sustained and slow release of the DTX from the spacers and showed a better response in suppressing the tumor as opposed control mice with saline injections. Further experiments for studying the combined chemo-radiation therapy are underway. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A82.
Citation Format: Rajiv Kumar, Jodi E. Belz, Stacey Markovic, Houari Korideck, Wilfred F. Ngwa, Mark Niedre, Ross I. Berbeco, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’ implants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A82.
Copyright © November 2013, American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A82.
Citation Format: Rajiv Kumar, Jodi E. Belz, Stacey Markovic, Houari Korideck, Wilfred F. Ngwa, Mark Niedre, Ross I. Berbeco, Robert Cormack, Mike G. Makrigiorgos, Srinivas Sridhar. Localized tumor delivery of radiosensitizers and chemotherapeutics using ‘INCeRT’ implants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A82.
Copyright © November 2013, American Association for Cancer Research@techreport{sridhar2013metamaterials,
title = {Metamaterials and Conformal Antenna Technologies},
author = {Srinivas Sridhar and Mehmet Dokmeci and Hossein Mosallaei and Latika Menon and Jeffrey Sokoloff and Don Heiman},
year = {2013},
date = {2013-01-01},
institution = {DTIC Document},
abstract = {Meta-materials are artificially constructed materials. When electromagnetic waves propagate
through meta-materials they display properties different from those found in natural materials.
These different properties can include negative refraction (light is bent in the opposite direction
from that expected from general laws of physics), flat lens focusing and sub-wavelength
imaging. The use of meta-materials to direct electromagnetic beams is a highly promising
approach to overcome current limitations of conformal antennas by improving the radiation
characteristics of antenna elements, especially those at the edge of phased array antennas.
This project was centered on research and development of next generation metamaterials that are
needed in optical and microwave radar antenna technologies. By directing electromagnetic
beams, such materials can enormously improve detection the detection of enemy bodies and
satellite communication with aircraft.
During this performance period, groundbreaking results were obtained in the following areas:
• Metamaterial Optical Components
• Theory of metamaterials based optical components
• Metamaterials, Nanofabrication and Sensors
• Metamaterial Antennas
• Reviews
Our work in this area has led to several major results, reported in 26 completed papers, and 3
patent applications, resulted in several invited and contributed presentations at international
conferences and workshops, and has received extensive attention in the popular press, including
write-ups in Nature, R&D Magazine, and other web and print outlets. },
keywords = {},
pubstate = {published},
tppubtype = {techreport}
}
through meta-materials they display properties different from those found in natural materials.
These different properties can include negative refraction (light is bent in the opposite direction
from that expected from general laws of physics), flat lens focusing and sub-wavelength
imaging. The use of meta-materials to direct electromagnetic beams is a highly promising
approach to overcome current limitations of conformal antennas by improving the radiation
characteristics of antenna elements, especially those at the edge of phased array antennas.
This project was centered on research and development of next generation metamaterials that are
needed in optical and microwave radar antenna technologies. By directing electromagnetic
beams, such materials can enormously improve detection the detection of enemy bodies and
satellite communication with aircraft.
During this performance period, groundbreaking results were obtained in the following areas:
• Metamaterial Optical Components
• Theory of metamaterials based optical components
• Metamaterials, Nanofabrication and Sensors
• Metamaterial Antennas
• Reviews
Our work in this area has led to several major results, reported in 26 completed papers, and 3
patent applications, resulted in several invited and contributed presentations at international
conferences and workshops, and has received extensive attention in the popular press, including
write-ups in Nature, R&D Magazine, and other web and print outlets. @misc{campbell2013magnetic,
title = {Magnetic nanoplatforms for theranostic and multi-modal imaging applications},
author = {Robert B Campbell and Srinivas Sridhar},
year = {2013},
date = {2013-01-01},
abstract = {Disclosed are nanoparticle compositions comprising paramagnetic particles, radiolabels, fluorophores, and/or positron emission tomography agents encapsulated within a biocompatible vehicle. In addition, methods of multi-modal diagnostic imaging and treating diseased tissues are disclosed, wherein the methods comprises administering a nanoparticle composition to a subject in which the nanoparticle composition comprises paramagnetic particles, radiolabels, fluorophores, and positron emission tomography agents encapsulated within a biocompatible vehicle.},
note = {US Patent App. 13/583,616},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{andersonour,
title = {Our thanks to all those who have helped with this issue of Nanomedicine. Listed below are authors, referees and others who have kindly given their time, effort and expertise; their generosity has helped establish this publication.},
author = {D Anderson and A Archakov and K Avgoustakis and A Baumgartner and R Bawa and M Bernardo and V Biricova and R Brayner and MW Brechbiel and J Buse and others},
year = {2012},
date = {2012-12-20},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{kumar2012comprehensive,
title = {Comprehensive evaluation of PEGylated gold nanorods for two photon photoluminescence image guided radiation therapy enhancement},
author = {Rajiv Kumar and Janki Patel and Houari Korideck and Ross I Berbeco and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
publisher = {American Association for Cancer Research},
abstract = {Nanoparticle formulations of gold have shown a tremendous potential in various biomedical applications. The use of high atomic number (Z) materials presents an attractive approach in enhancing the therapeutic efficacy of the radiation therapy. The high Z number for gold (Z=79) makes them an ideal candidate for radiosensitization enhancement. The ability of the anisotropic gold nanorods to sustain the resonating surface plasmon with minimal damping results in highly efficient two-photon induced photoluminescence imaging. Here we present the synthesis and in vitro characterization of PEGylated gold nanorods as efficient radiosensitizing agents which can be imaged using inherent two-photon photoluminescence without a conjugated fluorophore. We have synthesized gold nanorods with an aspect ratio of 2.5 and functionalized the surface with different ratios of methoxy and amine PEG for modulating the charge and imparting the functional groups. The cellular uptake behavior in prostate cancer cell line PC3 was studied and the results indicated a robust uptake of the amine functionalized nanorods. The quantitative estimation of the nanorods uptake was performed with BCA assay as amount of nanorods present in per microgram of protein. Two photon photoluminescence imaging also confirmed a robust cellular uptake of the amine functionalized nanorods. The radiation damage enhancement of the gold nanorods was confirmed using PC3 cells. The cells treated with gold nanorods were irradiated with kilovoltage X-rays. A γH2AX assay was used for quantitation of the DNA damage with and without nanorods as controls. The results indicated an increased highly efficient DNA damage in cells treated with gold nanorods. The outcome of this research will enable further application of targeted nanorods in advanced animal models as efficient radiation dose enhancement agents wherein two-photon photoluminescence imaging will provide a real time assessment of the therapeutic response and disease progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1472. doi:1538-7445.AM2012-1472
©2012 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1472. doi:1538-7445.AM2012-1472
©2012 American Association for Cancer Research@misc{kumar2012nanocoated,
title = {Nanocoated brachytherapy spacers eluting radiosensitizers for biological in situ image-guided radiation therapy of prostate cancer},
author = {Rajiv Kumar and Apurva Kulkarni and Dattatri Nagesha and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
publisher = {American Association for Cancer Research},
abstract = {The overall goal of this project is to develop means to locally radio-sensitize the prostate to enable prostate cancer (PCa) cure with the use of lower radiation doses, thereby leading to less rectal toxicity. This new approach for chemoradiation therapy (CRT), termed Biological In-Situ Image Guided Radiation Therapy BIS-IGRT, involves the coating of spacers routinely used during prostate I-125-based brachytherapy with radiosensitizing drugs (e.g. docetaxel DTX for PCa). This approach provides localized in-situ delivery of the sensitizer to the tumor and avoids the toxicity associated with current systemic delivery of radiosensitizers. BIS-IGRT adds radiosensitization capability to the standard brachytherapy procedure and with minimal additional inconvenience to the patient. Current CRT with adjuvant systemic chemotherapy does not provide the sustained delivery and drug concentration needed for efficient radiosensitization. Thereby BIS-IGRT improves the therapeutic ratio of radiation therapy without introducing additional patient interventions over current brachytherapy procedures. We have established the following: 1. We have shown through modeling that drug distributions can be achieved that can lead to increased efficiency of image-guided brachytherapy (drug-coated spacers) or image guided external beam therapy (drug-coated fiducials). 2. Doxorubicine-coated fiducials (Dox/PLGA-PEG/CHIT) show release characteristics over 40 days in aqueous media, which is tailored to the time scales required for BIS-IGRT. The cytotoxicity of Dox/ PLGA-PEG NP is comparable to that of free Dox, so that there is no reduction of activity upon encapsulation in the NP. 3. Localized bolus injection of dye-loaded PLGA-PEG nanoparticles (NPs) distributes within 24 hours throughout the tumor, indicating that the sustained release from coated brachytherapy spacers has the potential to achieve the desired biological dose-painting of the tumor. BIS-IGRT could proffer radiation oncologists and medical physicists with a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This new treatment approach would be of crucial benefit for patients with local relapse who require salvage radiotherapy but have reached their radiotherapy normal tissue dose limits. BIS-IGRT can still be accompanied by IV administration of chemotherapeutics, particularly for micro-metastasis, so that existing therapeutic approaches are not compromised. In addition BIS-IGRT could potentially become a mainstream treatment for patients newly diagnosed with prostate or other cancers, where radiation therapy is a common treatment modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1473. doi:1538-7445.AM2012-1473
©2012 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1473. doi:1538-7445.AM2012-1473
©2012 American Association for Cancer Research@article{kumar2012vitro,
title = {In vitro evaluation of theranostic polymeric micelles for imaging and drug delivery in cancer},
author = {Rajiv Kumar and Apurva Kulkarni and Dattatri K Nagesha and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
journal = {Theranostics},
volume = {2},
number = {7},
pages = {714},
publisher = {Ivyspring International Publisher},
abstract = {We describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
For the past decade engineered nanoplatforms have seen a momentous progress in developing a multimodal theranostic formulation which can be simultaneously used for imaging and therapy. In this report we describe the synthesis and application of theranostic phospholipid based polymeric micelles for optical fluorescence imaging and controlled drug delivery. CdSe quantum dots (QDs) and anti-cancer drug, doxorubicin (Dox), were co-encapsulated into the hydrophobic core of the micelles. The micelles are characterized using optical spectroscopy for characteristic absorbance and fluorescence features of QDs and Dox. TEM and DLS studies yielded a size of <50 nm for the micellar formulations with very narrow size distribution. A sustained release of the drug was observed from the co-encapsulated micellar formulation. In vitro optical fluorescence imaging and cytotoxicity studies with HeLa cell line demonstrated the potential of these micellar systems as efficient optical imaging and therapeutic probes.
Keywords: Theranostic Polymeric Micelles, Imaging, Drug Delivery, Cancer
@article{berbeco2012dna,
title = {DNA damage enhancement from gold nanoparticles for clinical MV photon beams},
author = {Ross I Berbeco and Houari Korideck and Wilfred Ngwa and Rajiv Kumar and Janki Patel and Srinivas Sridhar and Sarah Johnson and Brendan D Price and Alec Kimmelman and Mike G Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {Radiation research},
volume = {178},
number = {6},
pages = {604--608},
publisher = {The Radiation Research Society},
abstract = {OTHER| NOVEMBER 13 2012
DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams
Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos
Radiat Res (2012) 178 (6): 604–608.
https://doi.org/10.1667/RR3001.1
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In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams
Ross I. Berbeco; Houari Korideck; Wilfred Ngwa; Rajiv Kumar; Janki Patel; Srinivas Sridhar; Sarah Johnson; Brendan D. Price; Alec Kimmelman; G. Mike Makrigiorgos
Radiat Res (2012) 178 (6): 604–608.
https://doi.org/10.1667/RR3001.1
Share Icon
Share
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Tools
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In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by γ-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy.@article{yavuzcetin2012photonic,
title = {Photonic crystal fabrication in lithium niobate via pattern transfer through wet and dry etched chromium mask},
author = {Ozgur Yavuzcetin and Herman P Novikov and Rebecca L Dally and Sean T Malley and Nicholas R Perry and Birol Ozturk and Srinivas Sridhar},
year = {2012},
date = {2012-01-01},
journal = {Journal of Applied Physics},
volume = {112},
number = {7},
pages = {074303},
publisher = {American Institute of Physics},
abstract = {The need to fabricate photonic crystals from lithium niobate (LN) with accurate feature sizes is important to the development of optoelectronic devices. This paper reports a fabrication process to dry etch X-cut LN at a submicron scale using electron beam lithography and chromium as a hard mask. The chromium mask was used for both dry-etching and wet-etching in a unique method. Problems and solutions found during fabrication are presented. Arrays consisting of 400 nm diameter holes with a high aspect ratio were etched in LN, creating photonic crystals modeled to transmit light in the infrared spectrum.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{berbeco2012tu,
title = {TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations},
author = {R Berbeco and H Korideck and W Ngwa and R Kumar and J Patel and S Sridhar and S Johnson and B Price and A Kimmelman and M Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {Medical Physics},
volume = {39},
number = {6Part23},
pages = {3900--3901},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{ngwa2012vitro,
title = {In vitro dose enhancement from gold nanoparticles during low-dose-rate gamma irradiation with I-125 brachytherapy seeds},
author = {W Ngwa and H Korideck and A Kimmelman and AI Kassis and R Kumar and S Sridhar and M Makrigiorgos and RA Cormack},
year = {2012},
date = {2012-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {84},
number = {3},
pages = {S134},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.
Materials/Methods
HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.
Results
From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.
Conclusions
Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent studies have predicted substantial dose enhancement to tumors when gold nanoparticles (AuNP) are employed as adjuvants to radiation therapy at kV energies. Because the enhancement results from processes at kV energies, some studies proposed gold nanoparticle-aided brachytherapy as a radiation therapy approach with potential to meet technical and clinical requirements for implementation. To the best of our knowledge, there has been no study providing clear experimental evidence to corroborate the substantial dose enhancement predictions when irradiating with low dose rate gamma photons from brachytherapy sources. This study investigates the in vitro dose enhancement of AuNP during irradiation of cancer cells by I-125 low dose rate brachytherapy sources.
Materials/Methods
HeLa cell cultures were incubated with and without gold nanoparticles (AuNP) in alternate wells of an 8 well-chamber slide; 4 wells on each slide had cell cultures with AuNP while 4 wells contained cell cultures with no AuNP. Two slides were prepared for each experiment: one slide to be irradiated while the other serves as sham-irradiation control. The cells were irradiated with gamma photons from I-125 brachytherapy seeds in a plaque contained in a custom-built irradiation jig. The plaque was designed to achieve a relatively homogeneous dose distribution in the plane of the cell culture slide. Four sets of irradiation experiments were conducted at 370C at dose rates ranging from 2.1 cGy/hr to 4.5 cGy/hr. The dose rates were varied by varying the height of the cell culture slide above the plaque containing the I-125 seeds. Residual gammaH2AX was measured 24 hours after irradiation and used to compare the dose response of the cells with and without AuNP. In addition, the relative dose enhancement factor (DEF), representing the ratio of the dose to the cells with and without the presence of AuNP, was estimated from the data.
Results
From the dose response behavior, the results show that the biologic effect when irradiating with 0.2 mg/mL concentration of AuNP is up to 2.3 times greater than without AuNP. This major increase in radiation damage to cancer cells incubated with AuNP corresponds to an estimated DEF of over 3.5.
Conclusions
Our findings provide the first experimental evidence of substantial dose enhancement from gold nanoparticles during low dose rate gamma irradiation from brachytherapy sources. These in vitro study results provide impetus for further preclinical and clinical investigations in the development of gold nanoparticle-aided brachytherapy.@article{cormack2012locally,
title = {Locally Drug Enhanced Brachytherapy: A Comparison of 2 Approaches Based on Biologically Effective Dose},
author = {R Cormack and P Nguyen and AV D'Amico and S Sridhar and GM Makrigiorgos},
year = {2012},
date = {2012-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {84},
number = {3},
pages = {S854--S855},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.
Materials/Methods
The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.
Results
The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.
Conclusions
Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Permanent prostate brachytherapy may be enhanced by delivering radiosensitizer to the target during the implant process. Nanoparticles released from a substrate can deliver drug over an extended period of time and can be engineered to adjust their diffusion parameters. Nanoparticle eluting polymers have been proposed to coat radioactive sources or to form brachytherapy spacers as a way of delivering drug to the prostate. This work determines whether it is preferable to deliver radiosensitizer from sources or spacers.
Materials/Methods
The relative effectiveness of spacers or sources as sources of sensitizer was evaluated by comparing biologic effective dose (BED) of the combined effect of radiation and drug distributions within the prostate. Treatment plans of six patients receiving 125I prostate implants were analyzed under an IRB approved protocol. Target contours were extracted as were the locations of radioactive sources and spacers. Radiation dose was calculated according to AAPM TG43 methodology. Drug distributions were calculated from a solution of the diffusion equation, relative to the steady state concentration at the eluter's surface, for a range of diffusion-elimination modulus (φb) values and concentration needed for maximum sensitization (Cs). φb is viewed as a variable because the properties of the nanoparticles can be adjusted to affect diffusion and time of residence. Cs is treated as a variable because the amplitude of the drug distribution depends on the capacity of the implanted object and the time frame of release. BED calculations of the composite effect were done. The calculations were compared to an approach where the location of the spacers was allowed to be adjusted.
Results
The ratio of the BED for the two delivery approaches is presented in the 2D parameter space of φb and Cs. A full sensitization region, corresponding to low values of φb and Cs, shows no difference between approaches. The majority of the remaining parameter space, showed that using spacers to radiosensitize results in a greater BED. Changing the spacer locations from fixed by the treatment plan to adjustable allowed further increase of BED.
Conclusions
Using brachytherapy spacers as a vehicle to deliver radiosensitizing nanoparticles offers a greater potential to increase the effectiveness of prostate brachytherapy by in-situ radiosensitization. Further increase was achieved by treating spacer location as planning parameter. Using implanted non-radioactive devices for local radiosensitization suggests the potential of planned chemical distributions in conjunction with radiation planning to produce an optimal combined result.@article{H.Lewisa2011,
title = {Thermomagnetic determination of Fe3O4 magnetic nanoparticle diameters for biomedical applications},
author = {Brian D.Plouffea and Dattatri K.Nagesha and Robert S.DiPietro and Srinvas Sridhar and Don Heimand and Shashi K.Murthya and Lewis H.Lewisa
},
doi = {S0304885311002423},
year = {2011},
date = {2011-09-01},
journal = {Journal of Magnetism and Magnetic Materials},
volume = {323},
number = {17},
pages = {2310-2317},
abstract = {The utility and promise of magnetic nanoparticles (MagNPs) for biomedicine rely heavily on accurate determination of the particle diameter attributes. While the average functional size and size distribution of the magnetic nanoparticles directly impact the implementation and optimization of nanobiotechnology applications in which they are employed, the determination of these attributes using electron microscopy techniques can be time-consuming and misrepresentative of the full nanoparticle population. In this work the average particle diameter and distribution of an ensemble of Fe3O4 ferrimagnetic nanoparticles are determined solely from temperature-dependent magnetization measurements; the results compare favorably to those obtained from extensive electron microscopy observations. The attributes of a population of biocompatible Fe3O4 nanoparticles synthesized by a thermal decomposition method are obtained from quantitative evaluation of a model that incorporates the distribution of superparamagnetic blocking temperatures represented through thermomagnetization data. The average size and size distributions are determined from magnetization data via temperature-dependent zero-field-cooled magnetization. The current work is unique from existing approaches based on magnetic measurement for the characterization of a nanoparticle ensemble as it provides both the average particle size as well as the particle size distribution.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{Makrigiorgos2011,
title = {Optimal drug release schedule for in-situ radiosensitization of image guided permanent prostate implants},
author = {Robert A. Cormack; Paul L. Nguyen; Anthony V. D'Amico; Sri Sridhar; Mike Makrigiorgos
},
doi = {10.1117/12.878139},
year = {2011},
date = {2011-03-03},
journal = {Proceedings Volume 7964, Medical Imaging 2011: Visualization, Image-Guided Procedures, and Modeling},
volume = {7964},
number = {2011},
abstract = {Planned in-situ radiosensitization may improve the therapeutic ratio of image guided 125I prostate brachytherapy. Spacers used in permanent implants may be manufactured from a radiosensitizer-releasing polymer to deliver protracted localized sensitization of the prostate. Such devices will have a limited drug-loading capacity, and the drug release schedule that optimizes outcome, under such a constraint, is not known. This work determines the optimal elution schedules for 125I prostate brachytherapy. The interaction between brachytherapy dose distributions and drug distribution around drug eluting spacers is modeled using a linear-quadratic (LQ) model of cell kill. Clinical brachytherapy plans were used to calculate the biologic effective dose (BED) for planned radiation dose distributions while adding the spatial distributions of radiosensitizer while varying the temporal release schedule subject to a constraint on the drug capacity of the eluting spacers. Results: The greatest increase in BED is achieved by schedules with the greatest sensitization early in the implant. Making brachytherapy spacers from radiosensitizer eluting polymer transforms inert parts of the implant process into a means of enhancing the effect of the brachytherapy radiation. Such an approach may increase the therapeutic ratio of prostate brachytherapy or offer a means of locally boosting the radiation effect without increasing the radiation dose to surrounding tissues.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{sridhar2011large,
title = {Large scale nanoelement assembly method for making nanoscale circuit interconnects and diodes},
author = {Srinivas Sridhar and Evin Gultepe and Dattatri Nagesha},
year = {2011},
date = {2011-02-01},
abstract = {Nanoelements such as single walled carbon nanotubes are assembled in three dimensions into a nanoscale template on a substrate by means of electrophoresis and dielectrophoresis at ambient temperature. The current-voltage relation indicates that strong substrate-nanotube interconnects carrying mA currents are established inside the template pores. The method is suitable for large-scale, rapid, three-dimensional assembly of 1,000,000 nanotubes per square centimeter area using mild conditions. Circuit interconnects made by the method can be used for nanoscale electronics applications.},
note = {US Patent App. 12/936,938},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@misc{sridhar2011magnetic,
title = {Magnetic nanoplatforms for tumor targeting, imaging and energy delivery},
author = {Srinivas Sridhar and Robert Campbell and Dattatri Nagesha and Evin Gultepe},
year = {2011},
date = {2011-01-01},
publisher = {American Association for Cancer Research},
abstract = {We have developed magnetic nano-liposomes (MNL), incorporating superparamagnetic iron oxide nanoparticles (SPION), that are versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. MNL are prepared with a formuation of DPPC:DOTAP:CHOL and DOPE-PEG5000. Incorporation of SPIONs results in MNL with mean diameter of 150-250 nm. MNL are easily taken up by B16-F10 melanoma, HUMVEC-D and breast cancer cell lines. They preferentially target the tumor vasculature as shown in a dorsal skin fold chamber using fluorescently labeled MNL. MNL display superparamagnetic response that is essential for magnetic targeting, MR contrast enhancement and magnetic heating.
MNL was administrated to SCID mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre-injection and post-injection MR images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In labeled MNL and amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations.
We have shown that tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2-fold greater accumulation by magnetic targeting.
111In radio-labeled MNL have been shown to enable multi-modal imaging in vivo using MRI and SPeCT/CT. The images show that an MNL bolus injected intra-tumorally was retained in the tumor 24 hours after injection. Application of a magnetic field enables redistribution of the MNL in the tumor.
These MNL are also responsive to ac magnetic fields applied using a Copper coil at 360 kHz and 170A driving current. Both hyperthermia (upto 45C) and thermo-ablative temperatures upto 90C were achieved in 10 – 30 minutes ex vivo in buffer. The results indicate high efficiency for magnetic heating using MNL (Specific Absorption Rate ∼ 104 W/kg) and demonstrate the capability to couple ac magnetic fields to MNL to achieve any set of temperatures needed for hyperthermia and thermal ablation.
To date there are no truly theranostic platforms that have been approved for clinical use that combine targeting, thermal heating and MRI imaging capabilities. Existing FDA approved magnetic nanoparticle formulations like ferridex and ferumoxytol, are optimized for MR imaging, and have not been shown to be usable for thermal therapy.The MNL platform is a novel nanoplatform combining multi-modal imaging capabilities, with magnetic targeting and thermal therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2011-380
©2011 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
MNL was administrated to SCID mouse with metastatic (B16-F10) melanoma grown in the right flank. Pre-injection and post-injection MR images were used to assess response to magnetic targeting effects. Biodistribution studies were conducted by 111In labeled MNL and amount of radioactivity recovered was used to confirm the effect of targeting for intratumoral administrations.
We have shown that tumor signal intensities in T2 weighted images decreased an average of 20±5% and T2* values decreased and average of 14±7ms in the absence of magnetic targeting. This compares to an average signal decrease of 57±12% and a decrease in T2* relaxation times of 27±8ms with the aid of external magnet showing up to 2-fold greater accumulation by magnetic targeting.
111In radio-labeled MNL have been shown to enable multi-modal imaging in vivo using MRI and SPeCT/CT. The images show that an MNL bolus injected intra-tumorally was retained in the tumor 24 hours after injection. Application of a magnetic field enables redistribution of the MNL in the tumor.
These MNL are also responsive to ac magnetic fields applied using a Copper coil at 360 kHz and 170A driving current. Both hyperthermia (upto 45C) and thermo-ablative temperatures upto 90C were achieved in 10 – 30 minutes ex vivo in buffer. The results indicate high efficiency for magnetic heating using MNL (Specific Absorption Rate ∼ 104 W/kg) and demonstrate the capability to couple ac magnetic fields to MNL to achieve any set of temperatures needed for hyperthermia and thermal ablation.
To date there are no truly theranostic platforms that have been approved for clinical use that combine targeting, thermal heating and MRI imaging capabilities. Existing FDA approved magnetic nanoparticle formulations like ferridex and ferumoxytol, are optimized for MR imaging, and have not been shown to be usable for thermal therapy.The MNL platform is a novel nanoplatform combining multi-modal imaging capabilities, with magnetic targeting and thermal therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2011-380
©2011 American Association for Cancer Research@inproceedings{lu2011slow,
title = {Slow light using negative metamaterials},
author = {WT Lu and YJ Huang and S Sridhar},
year = {2011},
date = {2011-01-01},
booktitle = {Active Photonic Materials IV},
volume = {8095},
pages = {80951D},
organization = {International Society for Optics and Photonics},
abstract = {A general overview of slow light waveguide structures made of negative metamaterials is presented. We discuss the conditions and the parameter space to achieve zero total energy flow and zero group velocity due to the degeneracy of forward and backward waves in waveguides cladded with single negative metamaterials. Absorptive loss plays a severely limiting role and can prevent achieving the zero group velocity condition. Gain can be introduced either in dielectric or negative metamaterials to restore the zero group velocity condition. This type of slow light waveguide has a large delay bandwidth product and is suitable for use in integrated optoelectronic circuits.
© (2011) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
© (2011) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.@article{savo2011observation,
title = {Observation of slow-light in a metamaterials waveguide at microwave frequencies},
author = {Salvatore Savo and BDF Casse and Wentao Lu and Srinivas Sridhar},
year = {2011},
date = {2011-01-01},
journal = {Applied Physics Letters},
volume = {98},
number = {17},
pages = {171907},
publisher = {American Institute of Physics},
abstract = {We report an experimental observation of slow-light in the GHz microwave regime utilizing the mechanism of the degeneracy of forward and backward waves in a planar waveguide consisting of a dielectric core cladded by single-negative metamaterial.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{ye2011tuning,
title = {Tuning the optical properties of metamaterials based on gold nanowire arrays embedded in alumina},
author = {Yong-Hong Ye and YJ Huang and WT Lu and BDF Casse and D Xiao and SP Bennett and D Heiman and L Menon and S Sridhar},
year = {2011},
date = {2011-01-01},
journal = {Optical Materials},
volume = {33},
number = {11},
pages = {1667--1670},
publisher = {North-Holland},
abstract = {We fabricated a series of gold nanowires/alumina composite films with different wire lengths. Optical transmission measurements confirmed that the composite films exhibit transverse and longitudinal surface plasmon resonances. We show that the wavelength of the longitudinal resonance is sensitive to nanowire length, while that of the transverse resonance is not. The experimental results are in agreement with the modeled results based on the Maxwell Garnett effective medium theory. Moreover, the window for negative refraction of the samples can be tuned in synchronism with the longitudinal resonance by the nanowire length.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{yavuzcetin2011conicity,
title = {Conicity and depth effects on the optical transmission of lithium niobate photonic crystals patterned by focused ion beam},
author = {Ozgur Yavuzcetin and Birol Ozturk and Dong Xiao and Srinivas Sridhar},
year = {2011},
date = {2011-01-01},
journal = {Optical Materials Express},
volume = {1},
number = {7},
pages = {1262--1271},
publisher = {Optical Society of America},
abstract = {We report on novel focused ion beam fabrication techniques that can greatly improve the optical performance of photonic crystal structures. The finite depth and conicity effects of holes and trenches in Lithium Niobate (LN) photonic crystals have been theoretically analyzed, showing that the conicity causes refraction into the bulk sample, resulting in high transmission loss and no useful spectral features. The techniques for reducing the conicity angle from 25° to 5° were explained for the focused ion beam (FIB) milled structures.
©2011 Optical Society of America},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
©2011 Optical Society of America@article{casse2011robust,
title = {Robust method to determine the resolution of a superlens by analyzing the near-field image of a two-slit object},
author = {BDF Casse and WT Lu and YJ Huang and S Sridhar},
year = {2011},
date = {2011-01-01},
journal = {arXiv preprint arXiv:1105.0182},
abstract = {In the last decade, metamaterials-based superlenses, with a resolution below Abbe's diffraction limit, have emerged. To obtain a rough estimate of the resolution of such superlenses, imaging of two subwavelength slits, separated by a subwavelength gap textit{d} is typically performed. The resolution Δ of the lens corresponds to the minimum possible gap dmin for which a distinct image of the two slits can be resolved (Δ∼dmin). In this letter, we present a more quantitative estimate of the resolution of manufactured lenses by fitting analytical near-field image profiles, obtained from imaging a two-slit object with a theoretical negative-index lens of known resolution, to experimental data. We conclude the discussion by applying our analytical method to 3 case examples of superlensing from the literature. As shown, this method is particularly attractive for rapidly assessing the performance of fabricated superresolution lenses.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{alvarado2011effects,
title = {Effects of fibronectin and vitronectin on human fetal osteoblast cell attachment and proliferation on nanostructured titania surfaces},
author = {Melissa Alvarado-Velez and Delva M Rivera-Chacon and Claudia Y Acevedo-Morantes and Latika Menon and Dattatri Nagesha and Evin Gultepe and Srinivas Sridhar and Jaime E Ramirez-Vick and Surinder P Singh},
year = {2011},
date = {2011-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {241},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@misc{sridhar2011radio,
title = {Radio-sensitizer eluting nanoporous coatings on fiducials markers: Biological in-situ dose-painting for IGRT},
author = {Srinivas Sridhar and Dattatri Nagesha and Dayane Tada and Rajiv Kumar and Mike G Makrigiorgos and Robert Cormack},
year = {2011},
date = {2011-01-01},
publisher = {American Association for Cancer Research},
abstract = {Image-guided radiation treatments routinely utilize implantable devices, such as radio-opaque fiducials or brachytherapy spacers, for improved spatial accuracy. We study the hypothesis that the therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) using local delivery of radiosensitizers embedded within nanoparticles and nanoporous polymer matrices coating gold fiducial markers. Biocompatible polymers loaded with model molecules were coated as a thin film on gold fiducials. The nanoporous morphology of the polymer coatings allowed the controlled release of the molecules and nanoparticles. Two experimental approaches were studied: (i) a free drug release system Doxorubicin, a hydrophilic drug in Poly(methyl methacrylate (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with Coumarin-6, a model for a fluorescent hydrophobic drug, in a chitosan matrix applied as fiducial coating. Temporal release kinetics measurements in buffer were carried out using fluorescence spectroscopy. For flat gold films and gold fiducials coated with Doxorubicin in PMMA matrix, an initial release of Dox within the first few hours was followed by a sustained release over the course of next 3 months. Release of Dox from within PMMA matrix is dependent on the concentration of Dox, ratio of PMMA/Dox, thickness of PMMA/Dox coating on gold surface. The release profile of coumarin-6 loaded nanoparticles from chitosan film on gold fiducials showed a continuous release of NPs from the coating during forty days. (63±10)% of NPs were released in twenty days. After that, the release became slower and additional 37% of release was observed after twenty-days. Spatial release profiles in an agarose phantom were also measured and compared with release kinetics models. Results show that dosage and rate of release of these radiosensitizers can be precisely tailored to achieve the desired release profile for BIS-IGRT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2011-2674
©2011 American Association for Cancer Research},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2674. doi:10.1158/1538-7445.AM2011-2674
©2011 American Association for Cancer Research@incollection{savo2011slow,
title = {SLOW LIGHT IN NEGATIVE PERMEABILITY METAMATERIAL WAVEGUIDES},
author = {Salvatore Savo and Wentao T Lu and Bernard Didier F Casse and Srinivas Sridhar},
year = {2011},
date = {2011-01-01},
booktitle = {Selected Topics In Photonic Crystals And Metamaterials},
pages = {373--387},
abstract = {The ability to slow and even stop-light is crucial for the realization of all-optical integrated circuitry. In this chapter we present a design approach for realizing slow-light devices in the microwave band of frequency. Slow light can be achieved in a simple planar waveguide cladded with single negative metamaterial. Our device consists of a planar waveguide having a dielectric core and a negative permeability metamaterial. The negative permeability is obtained by arranging periodically split ring resonators (SRRs). We introduce a theoretical model, valid for both TE and TM modes, which describes light propagation in planar waveguides with single negative cladding, then we propose a prototype structure for TE mode working at 9.87GHz. The current design strategy relies on numerical simulations of the electromagnetic properties of SRRs which provide the scattering parameters. A parameters retrieval method has been used to extract the design window for the permeability and the permittivity.},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
@article{cassesuperresolution,
title = {Superresolution imaging and superfocusing with negative-index metamaterials},
author = {Bernard Didier F Casse and Srinivas Sridhar},
year = {2010},
date = {2010-03-19},
abstract = {Developments in higher-resolution optics have often led to rapid scientific and technological progress in the life sciences and engineering. In 1873, Ernst Abbe showed1 that the spatial resolution of optical-imaging instruments is limited by diffraction because of the finite wavelength of light. Abbe’s diffraction-limit theory implies that the resolving power of optical components cannot be smaller than half the wavelength of the incident light. Nanoscale optical elements that can mold the flow of light offer the potential of entirely new modalities of superresolution imaging. With a vision to build superlenses capable of resolving subwavelength details, in the last decade the photonics community has focused on fabricating tiny metallic inclusions (or, closely related, plasmonic architectures) characterized by a negative index of refraction. 2 Unfortunately, such metamaterials suffer from material losses enhanced by resonances, leading to a degradation of functionality. Instead, our group has demonstrated successful performance of highly functional nanostructured metamaterials in ‘low-loss’ dielectric platforms such as metal-dielectric composites and III-V semiconductors (composed of indium phosphide/indium gallium arsenide phosphide: InP/InGaAsP). We recently reported the experimental realization of superresolution imaging with a low-loss 3D nanolens, 3 comprised of gold nanowires embedded in nanoporous alumina: see Figure 1 (right). This 3D nanolens, manufactured using a combination of bottom-up self-assembly and electrochemical process, transmits subwavelength details down to= 4 (: Wavelength) and over a significant distance of more than …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gultepe2010nanoporous,
title = {Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable devices},
author = {Evin Gultepe and Dattatri Nagesha and Srinivas Sridhar and Mansoor Amiji},
year = {2010},
date = {2010-01-01},
journal = {Advanced drug delivery reviews},
volume = {62},
number = {3},
pages = {305--315},
publisher = {Elsevier},
abstract = {The characteristics of nanoporous inorganic coatings on implants or on implantable devices are reviewed. The commonly used nanoporous materials, such as aluminum oxide (Al2O3), titanium oxide (TiO2) and porous silicon are highlighted with illustrative examples. The critical issues for sustained release systems are examined and the elution pro?les of nanoporous coatings are discussed. The available data shows that these systems can be used effectively for sustained release applications. They satisfy the basic biocompatibility tests, meet the requirements of drug loading and sustained release pro?les extending to several weeks and also are compatible with current implant technologies. Nanoporous inorganic coatings are well suited to provide improved ef?cacy and integration of implants in a variety of therapeutic situations.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{casse2010super,
title = {Super-resolution imaging using a three-dimensional metamaterials nanolens},
author = {BDF Casse and WT Lu and YJ Huang and E Gultepe and L Menon and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Applied Physics Letters},
volume = {96},
number = {2},
pages = {023114},
publisher = {American Institute of Physics},
abstract = {Super-resolution imaging beyond Abbe’s diffraction limit can be achieved by utilizing an optical medium or “metamaterial” that can either amplify or transport the decaying near-field evanescent waves that carry subwavelength features of objects. Earlier approaches at optical frequencies mostly utilized the amplification of evanescent waves in thin metallic films or metal-dielectric multilayers, but were restricted to very small thicknesses (⪡λ, wavelength) and accordingly short object-image distances, due to losses in the material. Here, we present an experimental demonstration of super-resolution imaging by a low-loss three-dimensional metamaterial nanolens consisting of aligned gold nanowires embedded in a porous alumina matrix. This composite medium possesses strongly anisotropic optical properties with negative permittivity in the nanowire axis direction, which enables the transport of both far-field and near-field components with low-loss over significant distances (>6λ), and over a broad spectral range. We demonstrate the imaging of large objects, having subwavelength features, with a resolution of at least λ/4 at near-infrared wavelengths. The results are in good agreement with a theoretical model of wave propagation in anisotropic media.
The authors would like to thank M. G. Silveirinha, D. Heiman, J. Sokoloff, and F. Camino for useful discussions and comments. This work was financially supported by the Air Force Research Laboratories, Hanscom through Grant No. FA8718-06-C-0045 and NSF through Grant No. PHY-0457002. The work was also performed in part at the Kostas Center at Northeastern University and the Center for Nanoscale Systems, a member of NNIN, which is supported by the National Science Foundation under NSF Award No. ECS-0335765. Research carried out in part at the Center for Functional Nanomaterials, Brookhaven National Laboratory, which is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The authors would like to thank M. G. Silveirinha, D. Heiman, J. Sokoloff, and F. Camino for useful discussions and comments. This work was financially supported by the Air Force Research Laboratories, Hanscom through Grant No. FA8718-06-C-0045 and NSF through Grant No. PHY-0457002. The work was also performed in part at the Kostas Center at Northeastern University and the Center for Nanoscale Systems, a member of NNIN, which is supported by the National Science Foundation under NSF Award No. ECS-0335765. Research carried out in part at the Center for Functional Nanomaterials, Brookhaven National Laboratory, which is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886.@article{stambaugh2010we,
title = {WE-E-204B-02: Release Kinetics of Radio-Sensitizers from Nanoporous Coatings on Gold Fiducials: Biological In-Situ Dose-Painting for IGRT},
author = {C Stambaugh and D Tada and D Nagesha and E Jost and C Levy and RA Cormack and M Makrigiorgos and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Medical Physics},
volume = {37},
number = {6Part13},
pages = {3437--3438},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{cormack2010drug,
title = {Drug Eluting Brachytherapy Spacers: A Potential for Biologically-Enhanced Brachytherapy},
author = {Robert A Cormack and Dattatri Nagesha and Evin Gultepe and Paul Nguyen and Anthony V D'Amico and Srinivas Sridhar and Mike Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {Brachytherapy},
volume = {9},
pages = {S48--S49},
publisher = {Elsevier},
abstract = {Purpose: Ultrasound-guided prostate brachytherapy routinely implants spacers between the 125I radiation sources, that provide no therapeutic benefit although they are essential to the technical completion of the implant. The spacers offer a vehicle for in-situ delivery of radio-sensitizer, or other agents, which could increase the biologic effective dose of the radiation. This work studies the achievable drug coverage as a function of the chemical and physical properties of the drugs and devices.
Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.
Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.
Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Materials and Methods: Fluorescent doxorubicin in a polymer suspension and gold substrate were used to evaluate the ability to create a radio-opaque drug eluter. Elution kinetics from polymer coating of gold substrate was measured via fluorescence spectrometry. An analytic solution to the diffusion elimination equation was used to perform computer modeling of drug distributions produced by configurations of eluters placed within ultrasound guided prostate implants. Measures of tumor coverage and normal tissue involvement are evaluated for multiple combinations of eluter sizes and diffusion elimination moduli φb.
Results: Timed-release of doxorubicin from a polymer coating on a gold substrate, as shown in the top half of the figure, is technically possible. The many spacers used in prostate brachytherapy are sufficient to sensitize a portion of the prostate with values of φb close to the calculated ones. The use of drug-eluting brachytherapy spacers would enable a more localized enhancement in biologic effective dose than what can be delivered by a local brachytherapy boost. The bottom half of the figure shows a prostate implant at treated at our institution and and how it could be locally enhanced with the addition of a small number of drug eluting spacers.
Conclusions: IGRT techniques, such as ultrasound-guided brachytherapy, already implant devices within tumors as part of the standard of care. These devices may be enhanced with drug-eluting coatings to provide an in-situ increase in biologic effective dose without increasing the physical dose involved in the therapy. Generalization of this biologically in-situ enhanced IGRT (BIS-IGRT) to other agents in combination with advances in biologic imaging may provide an opportunity for personalized biologically in-situ enhanced brachytherapy.@article{lu2010storing,
title = {Storing light in active optical waveguides with single-negative materials},
author = {WT Lu and YJ Huang and BDF Casse and RK Banyal and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Applied Physics Letters},
volume = {96},
number = {21},
pages = {211112},
publisher = {American Institute of Physics},
abstract = {We show that a nonresonant planar waveguide consisting of conventional dielectric cladded with single-negative materials supports degenerate propagating modes for which the group velocity and total energy flow can be zero if the media are lossless. Absorptive losses will destroy the zero-group velocity condition for real frequency/complex wave vector modes.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gultepe2010monitoring,
title = {Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution},
author = {Evin Gultepe and Francisco J Reynoso and Aditi Jhaveri and Praveen Kulkarni and Dattatri Nagesha and Craig Ferris and Mukesh Harisinghani and Robert B Campbell and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Nanomedicine},
volume = {5},
number = {8},
pages = {1173--1182},
publisher = {Future Medicine Ltd London, UK},
abstract = {The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. MR and biodistribution analysis clearly show the ef?cacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{makrigiorgos201040,
title = {40 poster: Biological In-Situ Dose Painting for IGRT (BIS-IGRT) by Use of Drug-Loaded Implantable Fiducials and Spacers},
author = {M Makrigiorgos and S Sridhar and A D’Amico and P Nguyen and R Cormack},
year = {2010},
date = {2010-01-01},
journal = {Radiotherapy and Oncology},
volume = {94},
pages = {S18},
publisher = {Elsevier},
abstract = {Conclusions: 18F-ML-10 holds promise for early detection of tumor response to radiation. Generating" Delta image" for mapping response is feasible, and these images may potentially be employed for planning a non-uniform dose administration and adjustment, conforming to differential radio-sensitivity of various regions within the tumor. Multi-center studies are ongoing to evaluate performance of 18F-ML-10 in predicting response of different tumors to radiation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{gultepe2010sustained,
title = {Sustained Drug Release from Non-eroding Nanoporous Templates},
author = {Evin Gultepe and Dattatri Nagesha and Bernard DF Casse and Ravinder Banyal and Trifon Fitchorov and Alain Karma and Mansoor Amiji and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Small},
volume = {6},
number = {2},
pages = {213--216},
publisher = {WILEY-VCH Verlag Weinheim},
abstract = {We present the results for the release of a model drug, doxorubicin (Dox), fromdifferent non-eroding nanopor- ous coatings. Detailed studies of drug release from these platforms in the form of anodic aluminum oxide (AAO) and anodic titaniumoxide (ATO)were carried out. We show that nanoporous surfaces can achieve a sustained release rate over periods of several weeks, similar to polymeric platforms but without the risk of delamination or leaching since they are not degradable. We show that the kinetics of the sustained release from these nanoporous platforms is well described by an activated surface-density-dependent desorptionmodel,which appears to be universal for non-eroding platforms.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{nagesha2010radiosensitizer,
title = {Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT)},
author = {DK Nagesha and DB Tada and CKK Stambaugh and E Gultepe and E Jost and CO Levy and R Cormack and GM Makrigiorgos and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Physics in Medicine & Biology},
volume = {55},
number = {20},
pages = {6039},
publisher = {IOP Publishing},
abstract = {The therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs) . In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer Poly(methyl methacrylate) (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{tada2010chitosan,
title = {Chitosan film containing poly (D, L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release},
author = {Dayane B Tada and Surinder Singh and Dattatri Nagesha and Evan Jost and Craig O Levy and Evin Gultepe and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Pharmaceutical research},
volume = {27},
number = {8},
pages = {1738--1745},
publisher = {Springer US},
abstract = {The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.
Purpose
To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.
Methods
Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).
Results
Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.
Conclusions
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose
To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.
Methods
Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).
Results
Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.
Conclusions
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.@article{lu2010slow,
title = {Slow light, open-cavity formation, and large longitudinal electric field on a slab waveguide made of indefinite permittivity metamaterials},
author = {WT Lu and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Physical Review A},
volume = {82},
number = {1},
pages = {013811},
publisher = {APS},
abstract = {The optical properties of slab waveguides made of indefinite permittivity (
ɛ
) materials (IEMs) are considered. In this medium, the real part of the transverse permittivity is negative while that of the longitudinal permittivity is positive. At any given frequency, the IEM waveguide supports an infinite number of transverse magnetic (TM) eigenmodes. For a slab waveguide with a fixed thickness, at most only one TM mode is forward wave. The remainder are backward waves which can have a very large phase index. At a critical thickness, the waveguide supports degenerate forward- and backward-wave modes with zero group velocity if loss is absent. Above the critical thickness, the waveguide supports complex-conjugate decay modes instead of propagating modes. The presence of loss in IEMs will lift the TM mode degeneracy, resulting in modes with finite group velocity. A feasible realization is proposed. The performance of the IEM waveguide is analyzed and possible applications are discussed, which are supported by numerical calculations. These slab waveguides can be used to make optical delay lines in optical buffers to slow down and trap light, to form open cavities, to generate strong longitudinal electric fields, and as phase shifters in optical integrated circuits. Although the presence of loss will hinder these applications, gain can be introduced to compensate the loss and enhance the performance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
ɛ
) materials (IEMs) are considered. In this medium, the real part of the transverse permittivity is negative while that of the longitudinal permittivity is positive. At any given frequency, the IEM waveguide supports an infinite number of transverse magnetic (TM) eigenmodes. For a slab waveguide with a fixed thickness, at most only one TM mode is forward wave. The remainder are backward waves which can have a very large phase index. At a critical thickness, the waveguide supports degenerate forward- and backward-wave modes with zero group velocity if loss is absent. Above the critical thickness, the waveguide supports complex-conjugate decay modes instead of propagating modes. The presence of loss in IEMs will lift the TM mode degeneracy, resulting in modes with finite group velocity. A feasible realization is proposed. The performance of the IEM waveguide is analyzed and possible applications are discussed, which are supported by numerical calculations. These slab waveguides can be used to make optical delay lines in optical buffers to slow down and trap light, to form open cavities, to generate strong longitudinal electric fields, and as phase shifters in optical integrated circuits. Although the presence of loss will hinder these applications, gain can be introduced to compensate the loss and enhance the performance.@article{cormack2010biological,
title = {Biological in situ dose painting for image-guided radiation therapy using drug-loaded implantable devices},
author = {Robert A Cormack and Srinivas Sridhar and Warren W Suh and Anthony V D'Amico and Mike G Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {76},
number = {2},
pages = {615--623},
publisher = {Elsevier},
abstract = {Implantable devices routinely used for increasing spatial accuracy in modern image-guided radiation treatments (IGRT), such as fiducials or brachytherapy spacers, encompass the potential for in situ release of biologically active drugs, providing an opportunity to enhance the therapeutic ratio.We model this new approach for two types of treatment. Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug prop- erties were tabulated. Four radiosensitizer-loaded fiducials provide adequate radiosensitization for 4-cm-diameter lung tumors, thus potentially boosting biologically equivalent doses in centrally located stereotactic body treated lesions. Similarly, multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of biologi- cally equivalent doses to fit requirements difficult to meet by using radiation alone, e.g., boosting a high-risk region juxtaposed to the urethra while respecting normal tissue tolerance of both the urethra and the rectum. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@misc{lu2010photonic,
title = {Photonic crystal devices using negative refraction},
author = {Wentao T Lu and Srinivas Sridhar and Plarenta Vodo and Patanjali Parimi and Yongjian Huang},
year = {2010},
date = {2010-01-01},
abstract = {Negative refraction in photonic crystals and diffraction grating is used to design plano-concave lenses to focus plane waves. Microwave experiments are carried out to demonstrate negative refraction and the performance of these lenses. Demonstration of negative refraction of visible light is also performed for the grism. These lenses can be used in optical circuits, astronomical applications, etc.},
note = {US Patent 7,808,716},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{cormack2010mo,
title = {MO-FF-A1-01: Optimal Schedule for Localized Radio-Sensitization of 125I Prostate Implants},
author = {R Cormack and P Nguyen and A D” Amico and S Sridhar and M Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {Medical Physics},
volume = {37},
number = {6Part26},
pages = {3361--3361},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{casse2010beating,
title = {Beating the diffraction limit using a 3D nanowires metamaterials nanolens},
author = {BDF Casse and WT Lu and YJ Huang and E Gultepe and L Menon and S Sridhar},
year = {2010},
date = {2010-01-01},
booktitle = {Frontiers in Optics},
pages = {FWO3},
organization = {Optical Society of America},
abstract = {Super-resolution imaging using a three-dimensional metamaterials nanolens has been recently reported [B. D. F. Casse et al. Appl. Phys. Lett. 96, 023114 (2010)]. Here, we present validation of the superresolution imaging by the nanolens through extensive control experiments.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{reynoso2010th,
title = {TH-D-201C-08: Multi-Modal MRI SPECT and CT Imaging of Theranostic Nanoplatforms},
author = {F Reynoso and E Gultepe and A Jhaveri and P Kulkarni and B Gershman and C Ferris and R Campbell and M Harisinghani and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Medical Physics},
volume = {37},
number = {6Part8},
pages = {3470--3470},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{casse2010superresolution,
title = {Superresolution Imaging Using a 3D Nanolens Made Up of Bulk Nanowires Metamaterials},
author = {Bernard Didier Frederic Casse and Wentao Lu and Yongjian Huang and Evin Gultepe and Latika Menon and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Bulletin of the American Physical Society},
volume = {55},
publisher = {APS},
abstract = {Superresolution Imaging Using a 3D Nanolens Made Up of Bulk
Nanowires Metamaterials1 BERNARD DIDIER FREDERIC CASSE, WENTAO LU, YONGJIAN HUANG, EVIN GULTEPE, LATIKA MENON, SRINIVAS
SRIDHAR, Northeastern University — We report superresolution imaging of large
objects, having sub-λ features, over significant distances (>> λ, wavelength) with
a resolution well below the diffraction limit in optics, using a metallic nanolens.
The metallic nanolens is composed of high aspect ratio gold nanowires embedded
in disordered porous alumina template matrix. This composite medium possesses
strongly anisotropic optical properties with negative permittivity in the nanowire
axis direction, which enables negative refraction, and transports both far-field and
near-field components with minimal distortions and with very lowattenuations. The
long-distance image transport mechanism is not based on resonances of materials parameters and thus the subwavelength imaging occurs with low loss (Figure-of-merit
(FOM) = Re(n)/Im(n) ∼ 12 (much higher than existing metamaterials)) and in
a broad spectral range. This nanolens not only exhibits superior optical properties
over existing metamaterials-based lenses, but can also be manufactured in large scale
(mm size), thereby offering significant potential for applications in optical storage
devices, nanolithography and biomedical imaging.
1This work was financially supported by the AFRL, Hanscom through grant no.
FA8718-06-C-0045 and the NSF through grant no. PHY-0457002.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Nanowires Metamaterials1 BERNARD DIDIER FREDERIC CASSE, WENTAO LU, YONGJIAN HUANG, EVIN GULTEPE, LATIKA MENON, SRINIVAS
SRIDHAR, Northeastern University — We report superresolution imaging of large
objects, having sub-λ features, over significant distances (>> λ, wavelength) with
a resolution well below the diffraction limit in optics, using a metallic nanolens.
The metallic nanolens is composed of high aspect ratio gold nanowires embedded
in disordered porous alumina template matrix. This composite medium possesses
strongly anisotropic optical properties with negative permittivity in the nanowire
axis direction, which enables negative refraction, and transports both far-field and
near-field components with minimal distortions and with very lowattenuations. The
long-distance image transport mechanism is not based on resonances of materials parameters and thus the subwavelength imaging occurs with low loss (Figure-of-merit
(FOM) = Re(n)/Im(n) ∼ 12 (much higher than existing metamaterials)) and in
a broad spectral range. This nanolens not only exhibits superior optical properties
over existing metamaterials-based lenses, but can also be manufactured in large scale
(mm size), thereby offering significant potential for applications in optical storage
devices, nanolithography and biomedical imaging.
1This work was financially supported by the AFRL, Hanscom through grant no.
FA8718-06-C-0045 and the NSF through grant no. PHY-0457002.@inproceedings{didier2010superresolution,
title = {Superresolution Imaging Using a 3D Nanolens Made Up of Bulk Nanowires Metamaterials},
author = {Bernard Didier Frederic Casse and Wentao Lu and Yongjian Huang and Evin Gultepe and Latika Menon and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
booktitle = {APS Meeting Abstracts},
abstract = {We report superresolution imaging of large objects, having sub-λ features, over significant distances (>>λ, wavelength) with a resolution well below the diffraction limit in optics, using a metallic nanolens. The metallic nanolens is composed of high aspect ratio gold nanowires embedded in disordered porous alumina template matrix. This composite medium possesses strongly anisotropic optical properties with negative permittivity in the nanowire axis direction, which enables negative refraction, and transports both far-field and near-field components with minimal distortions and with very lowattenuations. The long-distance image transport mechanism is not based on resonances of materials parameters and thus the subwavelength imaging occurs with low loss (Figure-of-merit (FOM) =Re(n)/Im(n)̃12 (much higher than existing metamaterials)) and in a broad spectral range. This nanolens not only exhibits superior optical properties over existing metamaterials-based lenses, but can also be manufactured in large scale (mm size), thereby offering significant potential for applications in optical storage devices, nanolithography and biomedical imaging.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@article{casse2009imaging,
title = {Imaging with subwavelength resolution by a generalized superlens at infrared wavelengths},
author = {BDF Casse and WT Lu and RK Banyal and YJ Huang and S Selvarasah and MR Dokmeci and CH Perry and S Sridhar},
year = {2009},
date = {2009-01-01},
journal = {Optics letters},
volume = {34},
number = {13},
pages = {1994--1996},
publisher = {Optical Society of America},
abstract = {We demonstrate experimentally negative refraction by a photonic crystal prism and imaging of a point source by a photonic crystal slab at 1.5 μm wavelength. The photonic crystal structures were nanofabricated in a InGaAsP/InP heterostructure platform, and optical characterization was performed using a near-field scanning optical microscope. By designing a suitable lens surface termination, an image spot size of 0.12λ^2 was achieved, demonstrating superlens imaging with subwavelength resolution well below Abbe's diffraction limit (0.5λ^2).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{lu2009slow,
title = {Slow microwave waveguide made of negative permeability metamaterials},
author = {Wentao T Lu and Savatore Savo and Didier B F Casse and Srinivas Sridhar},
year = {2009},
date = {2009-01-01},
journal = {Microwave and Optical Technology Letters},
volume = {51},
number = {11},
pages = {2705--2709},
publisher = {Wiley Subscription Services, Inc., A Wiley Company Hoboken},
abstract = {The framework for designing a slow light waveguide structure which operates in the GHz and up to THz frequencies is outlined. The design for the structure consists of a dielectric core layer cladded with negative permeability metamaterials. The parameter space for the metamaterial has been identified for the waveguide to stop light and the negative permeability is achieved by split‐ring resonator (SRR) metallic elements. A prototype structure operating at 8.5 GHz is proposed. Numerical simulations of electromagnetic waves interacting with SRRs have been performed to extract scattering parameters and a parameter retrieval method has been used to verify the designed window for negative permeability. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 2705–2709, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24727},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{nagesha2009functionalization,
title = {Functionalization-induced improvement in magnetic properties of Fe 3 O 4 nanoparticles for biomedical applications},
author = {Dattatri K Nagesha and Brian D Plouffe and Minh Phan and Laura H Lewis and Srinivas Sridhar and Shashi K Murthy},
year = {2009},
date = {2009-01-01},
journal = {Journal of Applied Physics},
volume = {105},
number = {7},
pages = {07B317},
publisher = {American Institute of Physics},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{sawant2009nanosized,
title = {Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles},
author = {Rishikesh M Sawant and Rupa R Sawant and Evin Gultepe and Dattatri Nagesha and Brigitte Papahadjopoulos-Sternberg and Srinivas Sridhar and Vladimir P Torchilin},
year = {2009},
date = {2009-01-01},
journal = {Journal of Nanoparticle Research},
volume = {11},
number = {7},
pages = {1777},
publisher = {Springer Netherlands},
abstract = {Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{lu2009slowb,
title = {Slow light, open cavity formation, and large longitudinal electric field on slab waveguide made of indefinite-index metamaterials},
author = {WT Lu and S Sridhar},
year = {2009},
date = {2009-01-01},
journal = {arXiv preprint arXiv:0902.4482},
abstract = {There is a strong interest in slow light structures and devices [1–10]. This is driven by the need for optical buffers and optical memory in optical integrated circuits and other applications. In order to have small group velocity, various methods have been exploited to engineer material and structural dispersions, such as electromagnetic induced transparency [11], coupled resonant structures [5, 12], and optical nonlinearity [3]. Tsakmakidis et al [6] proposed a new scheme to realize trapped rainbow by using negative-index metamaterials. This slow light waveguide requires its core layer to be made of double negative metamaterial (DNM) whose permittivity and permeability are both negative. It is quite a challenge to realize DNMs with very low loss [13] since even moderate loss will destroy the zero group velocity mode [14, 15]. Strictly speaking, when loss is present as is inevitable in passive systems, stop light is impossible. However, gain may be introduced to compensate loss and makes zero group velocity possible [16]. In this paper we consider planar waveguide made of the so-called indefinite-index media [17–20] whose permittivity and/or the permeability tensors are indefinite matrices. For an indefinite-index metamaterial (IIM), the dispersion is hyperbolic for one polarization and elliptical for the other. Negative refraction, superlens imaging, and hyperlens focusing [21, 22] can be realized by using IIMs. Nanowire waveguide made of IIM has been considered by Huang et al [23]. These indefinite-index waveguides can support both forward-and backwardwave modes. High phase index can be obtained for these guided modes. These waveguides …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{sridhar2009nanoplatforms,
title = {Nanoplatforms for Nanomedicine},
author = {S Sridhar},
year = {2009},
date = {2009-01-01},
abstract = {Biocompatible nanomaterials are key components of novel approaches to addressing the major problems of modern medicine. A variety of nanoplatforms have emerged that have resulted in dramatic developments in imaging, early diagnosis and targeted delivery of therapeutics. Several varieties of nanoplatforms: metal, semiconducting polymeric and magnetic nanoparticles, liposomes, micelles, and nanoassemblies, have been developed that can enable efficacious delivery of drugs, DNA or energy to localized sites such as tumors, using targeting agents such as antibodies or guided navigation using magnetic fields. The optical properties of these nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications. Magnetic nanoplatforms for theranostics combine multiple functionalities including imaging, magnetic guidance to the disease site, delivery of the drug payload through sustained as well as triggered drug release. Nanoporous coatings have been developed for implants, cardiovascular stents and fiducials used in image guided radio therapy. The non-erodable coatings show sustained release profiles that are comparable to those from erodible polymer platforms, but without the problems of delamination. A new doctoral program has also been established incorporating new courses and interdisciplinary research in nanomedicine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{makrigiorgos2009biological,
title = {Biological In Situ Dose-painting for Image-guided Radiation Therapy using Drug-loaded Implantable Devices},
author = {M Makrigiorgos and S Sridhar and W Suh and A D'Amico and R Cormack},
year = {2009},
date = {2009-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {75},
number = {3},
pages = {S711--S712},
publisher = {Elsevier},
abstract = {Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug properties were tabulated. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …
@article{cormack2009th,
title = {TH-D-210A-06: Drug Eluting Implanted Devices to Increase Biologic Effective Dose in Image Guided Radiation Therapy},
author = {RA Cormack and S Sridhar and D Nagesha and E Gultepe and W Suh and AV D'Amico and M Makrigiorgos},
year = {2009},
date = {2009-01-01},
journal = {Medical Physics},
volume = {36},
number = {6Part28},
pages = {2819--2819},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{casse2009metallic,
title = {Metallic Nanolens and III-V Nano-Optical Metamaterials Lenses for Subwavelength Imaging and Optoelectronics Applications},
author = {Bernard Didier Casse and Wentao T Lu and Yongjian Huang and Srinivas Sridhar},
year = {2009},
date = {2009-01-01},
booktitle = {Optics and Photonics for Advanced Energy Technology},
pages = {ThC4},
organization = {Optical Society of America},
abstract = {We report the experimental realization of a metallic nanolens for far-field subwavelength imaging and 3 innovative III-V nano-optical lenses based on negative-index phenomena for optoelectronics applications. This work was supported by AFRL and NSF.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@inproceedings{patel2009metallic,
title = {Metallic nanoparticles for biomedical imaging},
author = {Yogesh Patel and Sucharita Saha and Charles DiMarzio and D O'Malley and Dattatri Nagesha and Srinivas Sridhar},
year = {2009},
date = {2009-01-01},
booktitle = {2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro},
pages = {759--762},
organization = {IEEE},
abstract = {The plasmon resonance conditions in nano-sized materials leads to local field enhancement resulting in amplified response of various linear and nonlinear optical processes at the nano-scale. In this paper, metallic nanoparticles are imaged using several modalities – brightfield, confocal reflectance, two-photon, and second harmonic generation. Two examples are discussed . Au nanoparticles in the zebrafish spinal column, and Ag nanoparticles in fresh skin excisions. We show that the optical properties of noble-metal nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications.
},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
@misc{sridhar2009anisotropic,
title = {Anisotropic metal-dielectric metamaterials for broadband all-angle negative refraction and superlens imaging},
author = {Srinivas Sridhar and Wentao Lu},
year = {2009},
date = {2009-00-01},
abstract = {A metamaterial comprises a plurality of metallic nanowires embedded in a dielectric matrix. The metamaterial composite media provide broadband all-angle negative refraction and flat lens, superlens and curved hyperlens imaging in specific spectral regions over a wide range of frequencies including, for example, from deep infrared to ultraviolet frequencies.},
note = {US Patent App. 12/220,445},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
@article{menonnegative,
title = {Negative Index Metamaterials Based on Metal Nanowire Arrays Electrodeposited in Nanoporous Alumina Templates},
author = {L Menon and W Lu and A Friedman and S Bennett and D Heiman and S Sridhar},
year = {2008},
date = {2008-09-25},
abstract = {Negative index metamaterials are demonstrated based on metal-dielectric nanocomposites. The nanocomposites are prepared using a versatile bottom-up nanofabrication approach involving the incorporation of vertically aligned metal nanowires such as Au and Ag inside dielectric aluminum oxide nanotemplates. Aluminum oxide nanotemplates with specific pore dimensions are fabricated by means of electrochemical anodization. Following this, Au/Ag nanowires with specific wire dimensions are electrodeposited inside the pores. Optical absorbance measurements show resonance peaks corresponding to transverse and longitudinal surface plasmon modes. Peak position and intensity are found to be strongly dependent on nanocomposite dimensions, filling factor (ratio of the volume of metal versus the volume of dielectric) and angle of incidence with respect to the wire axis. A quantitative model based on …},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{lu2008electronic,
title = {Electronic structure: Wide-band, narrow-band, and strongly correlated systems-Superlens imaging theory for anisotropic nanostructured metamaterials with broadband all-angle negative refraction},
author = {WT Lu and S Sridhar},
year = {2008},
date = {2008-01-01},
journal = {Physical Review B Condensed Matter And Materials Physics},
volume = {78},
number = {23},
pages = {233101},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@article{lu2008superlens,
title = {Superlens imaging theory for anisotropic nanostructured metamaterials with broadband all-angle negative refraction},
author = {WT Lu and S Sridhar},
year = {2008},
date = {2008-01-01},
journal = {Physical Review B},
volume = {77},
number = {23},
pages = {233101},
publisher = {APS},
abstract = {We show that a metamaterial consisting of aligned metallic nanowires in a dielectric matrix has strongly anisotropic optical properties. For long wavelngths, the longitudinal SPR, the material exhibits positive transverse permittivity and negative longitudinal permittivity, relative to the nanowires axis, enabling the achievement of broadband all-angle negative refraction and superlens imaging. An imaging theory of superlens made of these media is established. High performance systems made with Au, Ag, or Al nanowires in nanoporous templates are designed and predicted to work from the infrared up to ultraviolet frequencies.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
@inproceedings{banyal2008experimental,
title = {Experimental realization of a generalized superlens using negative refraction at infrared wavelengths},
author = {Ravinder Banyal and BDF Casse and WT Lu and YJ Huang and S Selvarasah and M Dokmeci and CH Perry and S Sridhar},
year = {2008},
date = {2008-01-01},
booktitle = {APS Meeting Abstracts},
abstract = {We demonstrate experimentally using a near-field scanning optical microscope the imaging of a point source by a generalized superlens fabricated in InGaAsP/InP heterostructure at wavelengths around lambda= 1.5 mum. The theory of superlens imaging with lens equation u+ v= sigmad gives excellent explanation of wave refraction and imaging formation of our superlens with an effective lens property ε eff= 0.43. This can be used as the basis for design optical elements made of photonic crystals.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}