Nanomedicine is the application of nanotechnology to medicine.
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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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Baldwin, Paige; Orriols, Adrienne; Sridhar, Srinivas Combination nanotherapy using the PARP inhibitor talazoparib and cyclin dependent kinase inhibitor dinaciclib Miscellaneous 2019. Abstract | Tags: Nanomedicine Singh, Bijay; Abdelhalim, Mostafa; Warrington, Stephanee; Sridhar, Srinivas Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer Miscellaneous 2019. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Bal, Nandita; Cheng, Ming; Kumar, Rajiv; Sridhar, Srinivas; Ebong, Eno E In Vivo Endothelial Uptake of Nanoparticles: Impact of Disturbed Flow and Degraded Glycocalyx Inproceedings In: 2019 AIChE Annual Meeting, AIChE 2019. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Baldwin, Paige; Ohman, Anders; Medina, Jamie; Dinulescu, Daniela; Sridhar, Srinivas NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL Inproceedings In: CLINICAL CANCER RESEARCH, pp. 198–198, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2019. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Celluzzi, Antonella; Paolini, Alessandro; D’Oria, Valentina; Risoluti, Roberta; Materazzi, Stefano; Pezzullo, Marco; Casciardi, Stefano; Sennato, Simona; Bordi, Federico; Masotti, Andrea Biophysical and biological contributions of polyamine-coated carbon nanotubes and bidimensional buckypapers in the delivery of miRNAs to human cells Journal Article In: International journal of nanomedicine, vol. 13, pp. 1, 2018. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine, Opthalmology Thanh, Nguyen; Phuc, Xuan; Sridhar, Srinivas Nanoscale Magnetism in Next Generation Magnetic Nanoparticles Technical Report UNIVERSITY COLLEGE LONDON London United Kingdom 2018. Abstract | Tags: MRI, Nanomedicine 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. Abstract | Tags: Nanomedicine Amutha, S; Sridhar, S Green synthesis of magnetic iron oxide nanoparticle using leaves of Glycosmis mauritiana and their antibacterial activity against human pathogens Journal Article In: Journal of Innovations in Pharmaceutical and Biological Sciences, vol. 5, pp. 22–26, 2018. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Baldwin, Paige; Kumar, Rajiv; Sridhar, Srinivas Targeted nanotherapy using the PARP inhibitor talazoparib for breast cancer treatment Miscellaneous 2018. Abstract | Tags: Nanomedicine 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 Inproceedings In: MEDICAL PHYSICS, pp. E535–E535, WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA 2018. Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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). Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Belz, Jodi; Castilla-Ojo, Noelle; Sridhar, Srinivas; Kumar, Rajiv Radiosensitizing silica nanoparticles encapsulating docetaxel for treatment of prostate cancer Incollection In: Cancer Nanotechnology, pp. 403–409, Humana Press, New York, NY, 2017. Abstract | Tags: Nanomedicine Baldwin, Paige; Tangutoori, Shifalika; Sridhar, Srinivas Generation of Dose--Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations Incollection In: Cancer Nanotechnology, pp. 337–342, Humana Press, New York, NY, 2017. Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine Baldwin, Paige; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER Miscellaneous 2017. Abstract | Tags: Nanomedicine Baldwin, Paige; Kumar, Rajiv; Favours, Edward; Liby, Karen; Kurmasheva, Raushan; Kozono, David; Sridhar, Srinivas Nanoformulated Talazoparib and Olaparib for enhanced delivery Miscellaneous 2017. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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. Abstract | Tags: Nanomedicine 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 Inproceedings In: CANCER RESEARCH, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2017. Abstract | Tags: Nanomedicine 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. Tags: Nanomedicine@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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
@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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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{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 = {Nanomedicine},
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@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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
@article{celluzzi2018biophysical,
title = {Biophysical and biological contributions of polyamine-coated carbon nanotubes and bidimensional buckypapers in the delivery of miRNAs to human cells},
author = {Antonella Celluzzi and Alessandro Paolini and Valentina D’Oria and Roberta Risoluti and Stefano Materazzi and Marco Pezzullo and Stefano Casciardi and Simona Sennato and Federico Bordi and Andrea Masotti},
year = {2018},
date = {2018-01-01},
journal = {International journal of nanomedicine},
volume = {13},
pages = {1},
publisher = {Dove Press},
abstract = {Recent findings in nanomedicine have revealed that carbon nanotubes (CNTs) can be used as potential drug carriers, therapeutic agents and diagnostics tools. Moreover, due to their ability to cross cellular membranes, their nanosize dimension, high surface area and relatively good biocompatibility, CNTs have also been employed as a novel gene delivery vector system. In our previous work, we functionalized CNTs with two polyamine polymers, polyethyleneimine (PEI) and polyamidoamine dendrimer (PAMAM). These compounds have low cytotoxicity, ability to conjugate microRNAs (such as miR-503) and, at the same time, transfect efficiently endothelial cells. The parameters contributing to the good efficiency of transfection that we observed were not investigated in detail. In fact, the diameter and length of CNTs are important parameters to be taken into account when evaluating the effects on drug delivery efficiency. In order to investigate the biophysical and biological contributions of polymer-coated CNTs in delivery of miRNAs to human cells, we decided to investigate three different preparations, characterized by different dimensions and aspect ratios. In particular, we took into account very small CNTs, a suspension of CNTs starting from the commercial product and a 2D material based on CNTs (ie, buckypapers [BPs]) to examine the transfection efficiency of a rigid scaffold. In conclusion, we extensively investigated the biophysical and biological contributions of polyamine-coated CNTs and bidimensional BPs in the delivery of miRNAs to human cells, in order to optimize the transfection efficiency of these compounds to be employed as efficient drug delivery vectors in biomedical applications.},
keywords = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine, Opthalmology},
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 = {MRI, Nanomedicine},
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 = {Nanomedicine},
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.
@article{amutha2018green,
title = {Green synthesis of magnetic iron oxide nanoparticle using leaves of Glycosmis mauritiana and their antibacterial activity against human pathogens},
author = {S Amutha and S Sridhar},
year = {2018},
date = {2018-01-01},
journal = {Journal of Innovations in Pharmaceutical and Biological Sciences},
volume = {5},
pages = {22--26},
abstract = {The potential effect of Glycosmis mauritiana leaf extract for the formation of iron oxide nanoparticles and its application on antibacterial activity was discussed. The efficiency of G. mauritiana leaves are used as a bio-material for the first time as reducing agent. Synthesized iron oxide nanoparticles were characterized by UV–Vis spectrometry, DLS, XRD, FT-IR, SEM and TEM analysis. The results revealed that iron oxide nanoparticles has the absorption peak at 404 nm, spherical shaped and average size of particle is found to be below 100 nm. The green synthesized iron oxide nanoparticles showed good antibacterial activity against the tested pathogens. The present study highlights the potential application of iron oxide nanoparticles can be explored for biomedical industries.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
@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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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{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 = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
@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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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{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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
@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 = {Nanomedicine},
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.@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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}