Publications
Search Google Scholar | Search PubMed
61.
Baldwin, Paige; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas
Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER Miscellaneous
2017.
@misc{baldwin2017abstractb,
title = {Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER},
author = {Paige Baldwin and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {PURPOSE: PARP inhibitor therapy for ovarian cancer exploits the concept of synthetic lethality by taking advantage of defects in DNA damage repair pathways. Currently Olaparib is the only FDA-approved PARP inhibitor and is available as an oral dosage, which has plenty of advantages, but requires the drug to undergo first pass metabolism, inactivating a significant fraction of the dose. We have developed a nanoparticle delivery system to allow for local delivery of Olaparib directly to the intraperitoneal cavity.
METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging.
RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment.
CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy.
Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-080.
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
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.
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.
62.
Baldwin, Paige; Kumar, Rajiv; Favours, Edward; Liby, Karen; Kurmasheva, Raushan; Kozono, David; Sridhar, Srinivas
Nanoformulated Talazoparib and Olaparib for enhanced delivery Miscellaneous
2017.
@misc{baldwin2017nanoformulated,
title = {Nanoformulated Talazoparib and Olaparib for enhanced delivery},
author = {Paige Baldwin and Rajiv Kumar and Edward Favours and Karen Liby and Raushan Kurmasheva and David Kozono and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors such as Talazoparib and Olaparib exploit deficiencies in DNA repair pathways, making them attractive candidates for treatment of a number of different cancers. These drugs are particularly effective when used in combination with other DNA damaging agents such as chemotherapeutics and radiation therapy. Combination trials, however, have resulted in severe toxicities, necessitating either dose reduction or delay. Dose reduction leads to suboptimal dosing and provides little therapeutic benefit compared to monotherapy. Systemically administered nanoparticles offer a more effective way to selectively accumulate drugs in tumors and bypass toxicities associated with oral delivery. We have developed nanoparticle delivery systems for both Olaparib and Talazoparib in order to improve tumor accumulation while bypassing the toxicity associated with oral administration.
Methods: Lipid nanoformulations of Olaparib and Talazoparib have been developed and characterized in regard to size, surface charge, drug loading, release, and stability. NanoTalazoparib has been tested in vitro in breast cancer cell lines including W0069, W780, and HCC1937 which exhibit BRCA1 and 2 mutations, and NanoOlaparib in the lung cancer cell line Calu-6 which also has a defective FA-BRCA pathway. Mice have been treated with NanoOlaparib and NanoTalazoparib alone and in combination with radiation or temozolomide in order to evaluate toxicity. Therapeutic efficacy studies are currently underway.
Results: The nanoformulations have been formulated to encapsulate a clinically relevant dose of either Talazoparib or Olaparib and release at 37°C over a period of days, while remaining stable during storage at 4°C. In vitro, both nanoformulations show the same activity as free drug with IC50s in the nanomolar range for these cell lines with varying deficiencies in the BRCA pathway. Mice have shown no appreciable weight loss during treatment with either nanoformulation alone or in combination with other treatment modalities.
Conclusion: Nanoformulations of Talazoparib and Olaparib have been developed and characterized to demonstrate activity in vitro and tolerable doses in vivo. We have found that mice tolerate NanoTalazoparib at higher doses when combined with Temozolomide than when given oral Talazoparib. The sustained release from the nanoparticles allows for the nanoformulation to be administered less often than the daily administration for oral drug and the improved tolerability opens the door for combination therapy with both chemotherapeutics and radiation therapy. Therapeutic efficacy studies are underway and we expect that as a monotherapy NanoTalazoparib will be more effective at lower doses than oral Talazoparib, based on the longer circulation time and more selective accumulation in tumors. We also anticipate that combination therapy will be more effective with the nanoformulation, as the maximum tolerated dose is higher than that of the oral drug.
Citation Format: Paige Baldwin, Rajiv Kumar, Edward Favours, Karen Liby, Raushan Kurmasheva, David Kozono, Srinivas Sridhar. Nanoformulated Talazoparib and Olaparib for enhanced delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2017-3100
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
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.
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.
63.
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.
@misc{baig2017nanoformulation,
title = {Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts},
author = {Nabeela Baig and Rostislav Likhotvorik and Paige Baldwin and Srinivas Sridhar and Raushan Kurmasheva},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Ewing Family of tumors (EFT) comprises the fourth most common highly malignant childhood cancer. Although sustained event-free survival (EFS) can be achieved with intensive chemo-radiation therapy for patients with local-regional disease, this therapy is relatively ineffective in the treatment of metastatic disease with EFS of 12% at 5 years. Ewing sarcoma is characterized by a reciprocal translocation between chromosomes 11 and 22 that encodes a chimeric oncoprotein resulting from the fusion of EWSR1 to the FLI1 transcription factor in ~85% of tumors. Therapy for patients with EFT comprises surgery, intensive use of cytotoxic agents and radiation therapy. Dose intensification and dose compression has resulted in some improvement in outcome, but patents with advanced or metastatic disease at diagnosis still represent a challenge. Further, patients alive at 5 years from diagnosis still have a high probability of subsequent relapse. Further, long-term consequences of treatment included cardiac dysfunction, and secondary malignancies. Thus, more effective and less toxic therapies are required to treat patients with advanced disease.
Our studies, as part of the Pediatric Preclinical Testing Program (PPTP), identified the combination of the PARP inhibitor, talazoparib, with the DNA damaging agent temozolomide, as being highly synergistic in xenograft models of Ewing sarcoma, but not against other tumor types. In this study 5 of 10 Ewing tumor xenografts models showed dramatic regressions to the combination, while administered as single agents neither talazoparib or temozolomide were active. We have studied the talazoparib-temozolomide synergy in vitro, and results indicate that in models where there is no synergy as xenografts, the cell lines have either intrinsic resistance to talazoparib, temozolomide or both drugs. In mice, and in the clinical trial (NCT02116777), the talazoparib-temozolomide combination is toxic requiring a reduction in temozolomide dose to ~15% of its single maximum-tolerated dose.
We are exploring the use of nanoparticle-formulated talazoparib (npTLZ) developed by Nanomaterials Synthesis Laboratory at Northeastern University without tumor targeting or with antibody-mediated targeting to increase the tumor-drug delivery, reduce normal tissue toxicity (mainly thrombocytopenia), and potentially allow escalation of temozolomide dose. In the PPTP study, the MTD for temozolomide combined with free talazoparib (0.25 mg/kg PO BID daily x 5) was 12 mg/kg. Our recent data showed no toxicity of temozolomide at 66 mg/kg (PO daily x 5) in mice treated with npTLZ (0.5 mg/kg IV daily x 5), suggesting that npTLZ does not potentiate TMZ toxicity to normal mouse tissues. We anticipate that nanoparticle delivery of talazoparib combined with temozolomide will allow reduced toxicity while increasing the response rate for this combination in preclinical models of Ewing sarcoma.
Citation Format: Nabeela Baig, Rostislav Likhotvorik, Paige Baldwin, Srinivas Sridhar, Raushan Kurmasheva. Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5054. doi:10.1158/1538-7445.AM2017-5054
©2017 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
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.
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.
64.
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.
@article{hachani2017assessing,
title = {Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging},
author = {Roxanne Hachani and Martin A Birchall and Mark W Lowdell and Georgios Kasparis and Le D Tung and Bella B Manshian and Stefaan J Soenen and Willy Gsell and Uwe Himmelreich and Codi A Gharagouzloo and others},
year = {2017},
date = {2017-01-01},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {1--14},
publisher = {Nature Publishing Group},
abstract = {Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging (MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T2 - weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T2-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T2-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
65.
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.
@article{belz2017sustained,
title = {Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer},
author = {Jodi E Belz and Rajiv Kumar and Paige Baldwin and Noelle Castilla Ojo and Ana S Leal and Darlene B Royce and Di Zhang and Anne L van de Ven and Karen T Liby and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Theranostics},
volume = {7},
number = {17},
pages = {4340},
publisher = {Ivyspring International Publisher},
abstract = {Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
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.
66.
Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer Proceedings Article
In: CANCER RESEARCH, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2017.
@inproceedings{belz2017sustainedb,
title = {Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
booktitle = {CANCER RESEARCH},
volume = {77},
organization = {AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~…},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
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.
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.
67.
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.
@article{barlow2017high,
title = {High throughput microencapsulation of Bacillus subtilis in semi-permeable biodegradable polymersomes for selenium remediation},
author = {Jacob Barlow and Kevin Gozzi and Chase P Kelley and Benjamin M Geilich and Thomas J Webster and Yunrong Chai and Srinivas Sridhar and Anne L van de Ven},
year = {2017},
date = {2017-01-01},
journal = {Applied microbiology and biotechnology},
volume = {101},
number = {1},
pages = {455--464},
publisher = {Springer Berlin Heidelberg},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
68.
Kumar, Rajiv; Sridhar, Srinivas; Wilfred, NGWA; Cormack, Robert; Makrigiorgos, Gerassimos
Biopolymer-Nanoparticle Composite Implant for Tumor Cell Tracking Miscellaneous
2017, (US Patent App. 15/328,711).
@misc{kumar2017biopolymer,
title = {Biopolymer-Nanoparticle Composite Implant for Tumor Cell Tracking},
author = {Rajiv Kumar and Srinivas Sridhar and NGWA Wilfred and Robert Cormack and Gerassimos Makrigiorgos},
year = {2017},
date = {2017-00-01},
abstract = {A method of detecting migration of tumor cells is provided by implanting in a region of tumor cells one or more implants having a matrix material of a biocompatible and biodegradable polymer, and a plurality of nanoparticles dispersed within the matrix material and functionalized to bind tumor cells. Nanoparticles bound to the tumor cells that have migrated out of the region can be detected by various imaging modalities. The implant can be in the shape of a brachytherapy spacer or radiotherapy fiducial maker or can be a coating on a brachytherapy spacer or fiducial marker. A method of treating cancer is provided by implanting one or more brachytherapy spacers or fiducial markers including the matrix material and an anti-cancer therapeutic agent dispersed within the matrix material.},
note = {US Patent App. 15/328,711},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
A method of detecting migration of tumor cells is provided by implanting in a region of tumor cells one or more implants having a matrix material of a biocompatible and biodegradable polymer, and a plurality of nanoparticles dispersed within the matrix material and functionalized to bind tumor cells. Nanoparticles bound to the tumor cells that have migrated out of the region can be detected by various imaging modalities. The implant can be in the shape of a brachytherapy spacer or radiotherapy fiducial maker or can be a coating on a brachytherapy spacer or fiducial marker. A method of treating cancer is provided by implanting one or more brachytherapy spacers or fiducial markers including the matrix material and an anti-cancer therapeutic agent dispersed within the matrix material.
69.
Schuemann, Jan; Berbeco, Ross; Chithrani, Devika B; Cho, Sang Hyun; Kumar, Rajiv; McMahon, Stephen J; Sridhar, Srinivas; Krishnan, Sunil
Roadmap to clinical use of gold nanoparticles for radiation sensitization Journal Article
In: International Journal of Radiation Oncology* Biology* Physics, vol. 94, no. 1, pp. 189–205, 2016.
@article{schuemann2016roadmap,
title = {Roadmap to clinical use of gold nanoparticles for radiation sensitization},
author = {Jan Schuemann and Ross Berbeco and Devika B Chithrani and Sang Hyun Cho and Rajiv Kumar and Stephen J McMahon and Srinivas Sridhar and Sunil Krishnan},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {94},
number = {1},
pages = {189--205},
publisher = {Elsevier},
abstract = {The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.
70.
Baldwin, Paige; Ohman, Anders; Thong, Jeremy; Tangutoori, Shifalika; Dinulescu, Daniela; Sridhar, Srinivas
Abstract A03: PARP inhibitor nanotherapy for ovarian cancer. Miscellaneous
2016.
@misc{baldwin2016abstract,
title = {Abstract A03: PARP inhibitor nanotherapy for ovarian cancer.},
author = {Paige Baldwin and Anders Ohman and Jeremy Thong and Shifalika Tangutoori and Daniela Dinulescu and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Talazoparib and Olaparib are potent PARP inhibitors that are currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors typically results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (~120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, have been successfully formulated and tested in vitro on several cancer cell lines. KURAMOCHI, SKOV3, and OVSAHO were cultured in RPMI + 10% FBS. JHOS2 was cultured in RPMI + 10% FBS +1% Non-Essential Amino Acids. PA1, COV318, 403, 404, 4412, and 4306 were all cultured in DMEM + 10% FBS. 403 and 404 were derived from tumors of BRCA2-/-¬, PTEN-/-, and TP53mut mice. 4306 and 4412 4306 were developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP mice.
Dose Response: Cell lines were exposed to either Olaparib or NanoOlaparib concentrations ranging from 0 to 100 µM. Each cell line was treated for a total of four doubling cycles to ensure that the percent viability for each cell line was comparable. Cell viability was ascertained with an MTS assay, to measure the metabolic activity of the cells.
Pt synergism: The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from a delayed viability assay.
Results: In vitro studies PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci, each containing (CA)¬n microsatellites. Microsatellite instability has the potential to cause mutations in critical genes that contain coding repeat sequences. This suggests that the genetic instability in PA1 leads to downstream mutations conferring sensitivity to PARP inhibitors.
The murine cell lines, 403, 404 are the next most sensitive group to this treatment due to there triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. Loss of PTEN has been shown to lead to spontaneous DSBs, chromosomal instability, and defects in homologous recombination. While it was expected that cell lines with BRCA1/2 mutations would be some of the most sensitive to these treatments, the results indicate that BRCA mutations and deletions are just as susceptible as PTEN deletions while high genetic instability shows the greatest sensitivity.
NanoTalazoparib is 10-100 times more potent than Olaparib. The cell line dependence is similar to Olaparib except for the overall lower magnitudes.
In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut GEMM also showed good therapeutic response to i.p. administration.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nanotherapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A03.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Talazoparib and Olaparib are potent PARP inhibitors that are currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors typically results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (~120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, have been successfully formulated and tested in vitro on several cancer cell lines. KURAMOCHI, SKOV3, and OVSAHO were cultured in RPMI + 10% FBS. JHOS2 was cultured in RPMI + 10% FBS +1% Non-Essential Amino Acids. PA1, COV318, 403, 404, 4412, and 4306 were all cultured in DMEM + 10% FBS. 403 and 404 were derived from tumors of BRCA2-/-¬, PTEN-/-, and TP53mut mice. 4306 and 4412 4306 were developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP mice.
Dose Response: Cell lines were exposed to either Olaparib or NanoOlaparib concentrations ranging from 0 to 100 µM. Each cell line was treated for a total of four doubling cycles to ensure that the percent viability for each cell line was comparable. Cell viability was ascertained with an MTS assay, to measure the metabolic activity of the cells.
Pt synergism: The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from a delayed viability assay.
Results: In vitro studies PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci, each containing (CA)¬n microsatellites. Microsatellite instability has the potential to cause mutations in critical genes that contain coding repeat sequences. This suggests that the genetic instability in PA1 leads to downstream mutations conferring sensitivity to PARP inhibitors.
The murine cell lines, 403, 404 are the next most sensitive group to this treatment due to there triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. Loss of PTEN has been shown to lead to spontaneous DSBs, chromosomal instability, and defects in homologous recombination. While it was expected that cell lines with BRCA1/2 mutations would be some of the most sensitive to these treatments, the results indicate that BRCA mutations and deletions are just as susceptible as PTEN deletions while high genetic instability shows the greatest sensitivity.
NanoTalazoparib is 10-100 times more potent than Olaparib. The cell line dependence is similar to Olaparib except for the overall lower magnitudes.
In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut GEMM also showed good therapeutic response to i.p. administration.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nanotherapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A03.
©2016 American Association for Cancer Research.
Methods: Three nanoparticle (~120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, have been successfully formulated and tested in vitro on several cancer cell lines. KURAMOCHI, SKOV3, and OVSAHO were cultured in RPMI + 10% FBS. JHOS2 was cultured in RPMI + 10% FBS +1% Non-Essential Amino Acids. PA1, COV318, 403, 404, 4412, and 4306 were all cultured in DMEM + 10% FBS. 403 and 404 were derived from tumors of BRCA2-/-¬, PTEN-/-, and TP53mut mice. 4306 and 4412 4306 were developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP mice.
Dose Response: Cell lines were exposed to either Olaparib or NanoOlaparib concentrations ranging from 0 to 100 µM. Each cell line was treated for a total of four doubling cycles to ensure that the percent viability for each cell line was comparable. Cell viability was ascertained with an MTS assay, to measure the metabolic activity of the cells.
Pt synergism: The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from a delayed viability assay.
Results: In vitro studies PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci, each containing (CA)¬n microsatellites. Microsatellite instability has the potential to cause mutations in critical genes that contain coding repeat sequences. This suggests that the genetic instability in PA1 leads to downstream mutations conferring sensitivity to PARP inhibitors.
The murine cell lines, 403, 404 are the next most sensitive group to this treatment due to there triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. Loss of PTEN has been shown to lead to spontaneous DSBs, chromosomal instability, and defects in homologous recombination. While it was expected that cell lines with BRCA1/2 mutations would be some of the most sensitive to these treatments, the results indicate that BRCA mutations and deletions are just as susceptible as PTEN deletions while high genetic instability shows the greatest sensitivity.
NanoTalazoparib is 10-100 times more potent than Olaparib. The cell line dependence is similar to Olaparib except for the overall lower magnitudes.
In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut GEMM also showed good therapeutic response to i.p. administration.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Daniela Dinulescu, Srinivas Sridhar. PARP inhibitor nanotherapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A03.
©2016 American Association for Cancer Research.
71.
Markovic, Stacey; Belz, Jodi; Kumar, Rajiv; Cormack, Robert A; Sridhar, Srinivas; Niedre, Mark
Near-infrared fluorescence imaging platform for quantifying in vivo nanoparticle diffusion from drug loaded implants Journal Article
In: International journal of nanomedicine, vol. 11, pp. 1213, 2016.
@article{markovic2016near,
title = {Near-infrared fluorescence imaging platform for quantifying in vivo nanoparticle diffusion from drug loaded implants},
author = {Stacey Markovic and Jodi Belz and Rajiv Kumar and Robert A Cormack and Srinivas Sridhar and Mark Niedre},
year = {2016},
date = {2016-01-01},
journal = {International journal of nanomedicine},
volume = {11},
pages = {1213},
publisher = {Dove Press},
abstract = {Drug loaded implants are a new, versatile technology platform to deliver a localized payload of drugs for various disease models. One example is the implantable nanoplatform for chemo-radiation therapy where inert brachytherapy spacers are replaced by spacers doped with nanoparticles (NPs) loaded with chemotherapeutics and placed directly at the disease site for long-term localized drug delivery. However, it is difficult to directly validate and optimize the diffusion of these doped NPs in in vivo systems. To better study this drug release and diffusion, we developed a custom macroscopic fluorescence imaging system to visualize and quantify fluorescent NP diffusion from spacers in vivo. To validate the platform, we studied the release of free fluorophores, and 30 nm and 200 nm NPs conjugated with the same fluorophores as a model drug, in agar gel phantoms in vitro and in mice in vivo. Our data verified that the diffusion volume was NP size-dependent in all cases. Our near-infrared imaging system provides a method by which NP diffusion from implantable nanoplatform for chemo-radiation therapy spacers can be systematically optimized (eg, particle size or charge) thereby improving treatment efficacy of the platform.
Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Drug loaded implants are a new, versatile technology platform to deliver a localized payload of drugs for various disease models. One example is the implantable nanoplatform for chemo-radiation therapy where inert brachytherapy spacers are replaced by spacers doped with nanoparticles (NPs) loaded with chemotherapeutics and placed directly at the disease site for long-term localized drug delivery. However, it is difficult to directly validate and optimize the diffusion of these doped NPs in in vivo systems. To better study this drug release and diffusion, we developed a custom macroscopic fluorescence imaging system to visualize and quantify fluorescent NP diffusion from spacers in vivo. To validate the platform, we studied the release of free fluorophores, and 30 nm and 200 nm NPs conjugated with the same fluorophores as a model drug, in agar gel phantoms in vitro and in mice in vivo. Our data verified that the diffusion volume was NP size-dependent in all cases. Our near-infrared imaging system provides a method by which NP diffusion from implantable nanoplatform for chemo-radiation therapy spacers can be systematically optimized (eg, particle size or charge) thereby improving treatment efficacy of the platform.
Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring
Keywords: optical imaging, fluorescence, drug delivery, brachytherapy, treatment monitoring
72.
Hau, Herman; Khanal, Dipesh; Rogers, Linda; Suchowerska, Natalka; Kumar, Rajiv; Sridhar, Srinivas; McKenzie, David; Chrzanowski, Wojciech
Dose enhancement and cytotoxicity of gold nanoparticles in colon cancer cells when irradiated with kilo-and mega-voltage radiation Journal Article
In: Bioengineering & translational medicine, vol. 1, no. 1, pp. 94–102, 2016.
@article{hau2016dose,
title = {Dose enhancement and cytotoxicity of gold nanoparticles in colon cancer cells when irradiated with kilo-and mega-voltage radiation},
author = {Herman Hau and Dipesh Khanal and Linda Rogers and Natalka Suchowerska and Rajiv Kumar and Srinivas Sridhar and David McKenzie and Wojciech Chrzanowski},
year = {2016},
date = {2016-01-01},
journal = {Bioengineering & translational medicine},
volume = {1},
number = {1},
pages = {94--102},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
73.
Sridhar, Srinivas; Petrov, Yury; Yavuzcetin, Ozgur; Chowdhury, Kaushik
Sensor system and process for measuring electric activity of the brain, including electric field encephalography Miscellaneous
2016, (US Patent App. 14/896,511).
@misc{sridhar2016sensor,
title = {Sensor system and process for measuring electric activity of the brain, including electric field encephalography},
author = {Srinivas Sridhar and Yury Petrov and Ozgur Yavuzcetin and Kaushik Chowdhury},
year = {2016},
date = {2016-01-01},
abstract = {A sensor system and process for measuring electromagnetic activity of a brain are provided. The system and process employ a sensor assembly having a plurality of electrodes arranged in a closely spaced arrangement and a processor to determine a weighted average of the signals indicative of an electric field generated by electromagnetic activity of the brain. The system provides a medical body area network of a subject including one or more of the sensor assemblies and one or more additional sensors, which may be within a smartphone or other wearable device.},
note = {US Patent App. 14/896,511},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
A sensor system and process for measuring electromagnetic activity of a brain are provided. The system and process employ a sensor assembly having a plurality of electrodes arranged in a closely spaced arrangement and a processor to determine a weighted average of the signals indicative of an electric field generated by electromagnetic activity of the brain. The system provides a medical body area network of a subject including one or more of the sensor assemblies and one or more additional sensors, which may be within a smartphone or other wearable device.
74.
Cormack, Robert A; Nguyen, Paul N; D'Amico, Anthony V; Sridhar, Srinivas; Makrigiorgos, Gerassimos
Localized Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants Journal Article
In: Brachytherapy, vol. 15, pp. S161–S162, 2016.
@article{cormack2016localized,
title = {Localized Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Robert A Cormack and Paul N Nguyen and Anthony V D'Amico and Srinivas Sridhar and Gerassimos Makrigiorgos},
year = {2016},
date = {2016-01-01},
journal = {Brachytherapy},
volume = {15},
pages = {S161--S162},
publisher = {Elsevier},
abstract = {Purpose
In-situ drug release concurrent with radiation therapy may enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.
Methods and Materials
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.
Results
The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.
Conclusions
Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose
In-situ drug release concurrent with radiation therapy may enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.
Methods and Materials
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.
Results
The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.
Conclusions
Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.
In-situ drug release concurrent with radiation therapy may enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. The drug distributions are expected to have a comparable, or greater spatial gradient than brachytherapy radiation distributions. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine whether drug eluting sources or spacers produce greater effect.
Methods and Materials
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Prostate geometry, source and spacer positions were extracted from treatment plans of 125I permanent prostate implants. Radiation doses were calculated according to AAPM TG 43 point source formalism. Drug concentrations were calculated using a steady state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (φb). Radiosensitization was assumed to be dependent on drug concentration up to a saturation concentration (csat). Effective dose, taken to be the product of dose and sensitization, was used as an objective function to determine the optimal configuration of drug eluters for a range of φb, csat and number of eluters (ne). The locations of ne eluters were determined by a genetic optimization algorithm maximizing effective dose. The drug eluter that produced the greatest effective dose were tallied for points in parameter space [φb, csat,ne] to determine the conditions where one approach is preferable.
Results
The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration released from the surface of the eluter and ne from 10 to 60 drug eluters. For the region of [φb, csat] space that results in a large fraction of the gland being maximally sensitized, drug eluting spacers or sources produce equal increase in biologic effect. In the majority of the remaining [φb, csat] space, drug eluting spacers result in a greater biologic effect than sources even where sources often produce greater maximal radio-sensitization. Placing drug eluting implants in planned locations throughout the prostate results in even greater sensitization than using only source or spacer locations.
Conclusions
Drug eluting brachytherapy spacers offer a means to increase the biologic effect of brachytherapy implants with no change in treatment process. Incorporating additional needles allows the freedom to place spacers independently of sources and increases effective dose with minor modifications of the implant process. Further work is needed to understand the in-vivo spatial distribution of drug around drug eluters, and to incorporate time dependence of both drug release and radiation dose.
75.
Belz, J; Kumar, R; Makrigiorgos, G; D'Amico, A; Nguyen, P; Cormack, R; Sridhar, S
WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer Journal Article
In: Medical physics, vol. 43, no. 6Part41, pp. 3823–3823, 2016.
@article{belz2016we,
title = {WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer},
author = {J Belz and R Kumar and G Makrigiorgos and A D'Amico and P Nguyen and R Cormack and S Sridhar},
year = {2016},
date = {2016-01-01},
journal = {Medical physics},
volume = {43},
number = {6Part41},
pages = {3823--3823},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
76.
Baldwin, Paige; Ohman, Anders; Thong, Jeremy; Tangutoori, Shifalika; van de Ven, Anne; Kumar, Rajiv; Dinulescu, Daniela; Sridhar, Srinivas
Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy Miscellaneous
2016.
@misc{baldwin2016nanoformulations,
title = {Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy},
author = {Paige Baldwin and Anders Ohman and Jeremy Thong and Shifalika Tangutoori and Anne van de Ven and Rajiv Kumar and Daniela Dinulescu and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity. Here we report the development of novel nanoformulations of Olaparib and Talazoparib to allow intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and tested in vitro and in vivo. Short-and long-term dose response with a panel of ovarian cancer cell lines were conducted. These cell lines include KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from BRCA2-/-, PTEN-/-, TP53mut mice, and 4306 and 4412, developed from conditional LSL-K-rasG12D/+, PTENloxP/loxP mice. Radiosensitization with NanoOlaparib was tested in the radiation resistant prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results: The murine cell lines 403 and 404 were highly sensitive to this treatment due to the mutations in BRCA2, PTEN, and TP53. 4412 and 4306 showed comparable sensitivity, suggesting that a PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50’s. Strong synergistic radiosensitization was observed in FK01 cells with NanoOlaparib.
Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib clearly shrinks tumors.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed for in vitro and in vivo studies. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and prostate cancers.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Anne van de Ven, Rajiv Kumar, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4335.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity. Here we report the development of novel nanoformulations of Olaparib and Talazoparib to allow intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and tested in vitro and in vivo. Short-and long-term dose response with a panel of ovarian cancer cell lines were conducted. These cell lines include KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from BRCA2-/-, PTEN-/-, TP53mut mice, and 4306 and 4412, developed from conditional LSL-K-rasG12D/+, PTENloxP/loxP mice. Radiosensitization with NanoOlaparib was tested in the radiation resistant prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results: The murine cell lines 403 and 404 were highly sensitive to this treatment due to the mutations in BRCA2, PTEN, and TP53. 4412 and 4306 showed comparable sensitivity, suggesting that a PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50’s. Strong synergistic radiosensitization was observed in FK01 cells with NanoOlaparib.
Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib clearly shrinks tumors.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed for in vitro and in vivo studies. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and prostate cancers.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Anne van de Ven, Rajiv Kumar, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4335.
©2016 American Association for Cancer Research.
Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and tested in vitro and in vivo. Short-and long-term dose response with a panel of ovarian cancer cell lines were conducted. These cell lines include KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from BRCA2-/-, PTEN-/-, TP53mut mice, and 4306 and 4412, developed from conditional LSL-K-rasG12D/+, PTENloxP/loxP mice. Radiosensitization with NanoOlaparib was tested in the radiation resistant prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results: The murine cell lines 403 and 404 were highly sensitive to this treatment due to the mutations in BRCA2, PTEN, and TP53. 4412 and 4306 showed comparable sensitivity, suggesting that a PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50’s. Strong synergistic radiosensitization was observed in FK01 cells with NanoOlaparib.
Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib clearly shrinks tumors.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed for in vitro and in vivo studies. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and prostate cancers.
Citation Format: Paige Baldwin, Anders Ohman, Jeremy Thong, Shifalika Tangutoori, Anne van de Ven, Rajiv Kumar, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations of PARP inhibitors Olaparib and Talazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4335.
©2016 American Association for Cancer Research.
77.
Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer Miscellaneous
2016.
@misc{belz2016sustained,
title = {Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2016},
date = {2016-01-01},
publisher = {American Association for Cancer Research},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for non-metastatic cancers. Here we report a novel biodegradable implant with the capability to encapsulate therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.
©2016 American Association for Cancer Research.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Sustained localized delivery of cancer therapeutics is a safe and effective unique option for non-metastatic cancers. Here we report a novel biodegradable implant with the capability to encapsulate therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.
©2016 American Association for Cancer Research.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.
©2016 American Association for Cancer Research.
78.
Cheng, Ming J; Kumar, Rajiv; Sridhar, Srinivas; Webster, Thomas J; Ebong, Eno E
Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting Journal Article
In: International journal of nanomedicine, vol. 11, pp. 3305, 2016.
@article{cheng2016endothelial,
title = {Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting},
author = {Ming J Cheng and Rajiv Kumar and Srinivas Sridhar and Thomas J Webster and Eno E Ebong},
year = {2016},
date = {2016-01-01},
journal = {International journal of nanomedicine},
volume = {11},
pages = {3305},
publisher = {Dove Press},
abstract = {Cardiovascular diseases are facilitated by endothelial cell (EC) dysfunction and coincide with EC glycocalyx coat shedding. These diseases may be prevented by delivering medications to affected vascular regions using circulating nanoparticle (NP) drug carriers. The objective of the present study was to observe how the delivery of 10 nm polyethylene glycol-coated gold NPs (PEG-AuNP) to ECs is impacted by glycocalyx structure on the EC surface. Rat fat pad endothelial cells were chosen for their robust glycocalyx, verified by fluorescent immunolabeling of adsorbed albumin and integrated heparan sulfate (HS) chains. Confocal fluorescent imaging revealed a ~3 µm thick glycocalyx layer, covering 75% of the ECs and containing abundant HS. This healthy glycocalyx hindered the uptake of PEG-AuNP as expected because glycocalyx pores are typically 7 nm wide. Additional glycocalyx models tested included: a collapsed glycocalyx obtained by culturing cells in reduced protein media, a degraded glycocalyx obtained by applying heparinase III enzyme to specifically cleave HS, and a recovered glycocalyx obtained by supplementing exogenous HS into the media after enzyme degradation. The collapsed glycocalyx waŝ2 µm thick with unchanged EC coverage and sustained HS content. The degraded glycocalyx showed similar changes in EC thickness and coverage but its HS thickness was reduced to 0.7 µm and spanned only 10% of the original EC surface. Both dysfunctional models retained six- to sevenfold more PEG-AuNP compared to the healthy glycocalyx. The collapsed glycocalyx permitted NPs to cross the glycocalyx into intracellular spaces, whereas the degraded glycocalyx trapped the PEG-AuNP within the glycocalyx. The repaired glycocalyx model partially restored HS thickness to 1.2 µm and 44% coverage of the ECs, but it was able to reverse the NP uptake back to baseline levels. In summary, this study showed that the glycocalyx structure is critical for NP uptake by ECs and may serve as a passive pathway for delivering NPs to dysfunctional ECs.
Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cardiovascular diseases are facilitated by endothelial cell (EC) dysfunction and coincide with EC glycocalyx coat shedding. These diseases may be prevented by delivering medications to affected vascular regions using circulating nanoparticle (NP) drug carriers. The objective of the present study was to observe how the delivery of 10 nm polyethylene glycol-coated gold NPs (PEG-AuNP) to ECs is impacted by glycocalyx structure on the EC surface. Rat fat pad endothelial cells were chosen for their robust glycocalyx, verified by fluorescent immunolabeling of adsorbed albumin and integrated heparan sulfate (HS) chains. Confocal fluorescent imaging revealed a ~3 µm thick glycocalyx layer, covering 75% of the ECs and containing abundant HS. This healthy glycocalyx hindered the uptake of PEG-AuNP as expected because glycocalyx pores are typically 7 nm wide. Additional glycocalyx models tested included: a collapsed glycocalyx obtained by culturing cells in reduced protein media, a degraded glycocalyx obtained by applying heparinase III enzyme to specifically cleave HS, and a recovered glycocalyx obtained by supplementing exogenous HS into the media after enzyme degradation. The collapsed glycocalyx waŝ2 µm thick with unchanged EC coverage and sustained HS content. The degraded glycocalyx showed similar changes in EC thickness and coverage but its HS thickness was reduced to 0.7 µm and spanned only 10% of the original EC surface. Both dysfunctional models retained six- to sevenfold more PEG-AuNP compared to the healthy glycocalyx. The collapsed glycocalyx permitted NPs to cross the glycocalyx into intracellular spaces, whereas the degraded glycocalyx trapped the PEG-AuNP within the glycocalyx. The repaired glycocalyx model partially restored HS thickness to 1.2 µm and 44% coverage of the ECs, but it was able to reverse the NP uptake back to baseline levels. In summary, this study showed that the glycocalyx structure is critical for NP uptake by ECs and may serve as a passive pathway for delivering NPs to dysfunctional ECs.
Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold
Keywords: glycocalyx, heparan sulfate, endothelial cells, NP, gold
79.
Kunjachan, S; Detappe, A; Kumar, R; Sridhar, S; Makrigiorgos, GM; Berbeco, R
PO-0983: Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy Journal Article
In: Radiotherapy and Oncology, vol. 119, pp. S477–S478, 2016.
@article{kunjachan2016po,
title = {PO-0983: Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy},
author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and GM Makrigiorgos and R Berbeco},
year = {2016},
date = {2016-01-01},
journal = {Radiotherapy and Oncology},
volume = {119},
pages = {S477--S478},
publisher = {Elsevier},
abstract = {Purpose or Objective: More than 50% all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation doses is strictly
restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016
_____________________________________________________________________________________________________
Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose or Objective: More than 50% all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation doses is strictly
restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016
_____________________________________________________________________________________________________
Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.
restricted by the proximal healthy tissues. Chemical/biological agents to augment the radiosensitization of cancer cells are limited by severe off-target toxicity concerns. We propose a dual-targeting strategy using tumor vasculartargeted gold nanoparticles (which amplify radiosensitization) combined with the conformal imageguided radiation therapy to induce tumor vascular disruption. This is a unique concept with a clear translational path. S478 ESTRO 35 2016
_____________________________________________________________________________________________________
Material and Methods: Chemically synthesized, RGD-/PEGfunctionalized gold nanoparticles (RGD:AuNP; ≈2 -3 nm) were characterized using STEM, TEM, and LIBS imaging. Following clonogenic assay, radiation damage was induced in Panc1 xenografts with 10 Gy and 220 kVp (Xtrahl, Inc). γ-H2AX, 3D-(confocal) vessel imaging and IHC were performed. Results: Tumor vessel-targeted gold nanoparticles were subjected to conformal image-guided irradiation in Panc-1 tumor xenograft to induce tumor vascular disruption. By specifically targeting the early angiogenic tumor endothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limits the penetration and permeation of anti-cancer drugs/ nanoparticles to the cancer cells - a limitation of current radiosensitization approaches. In vitro testing in HUVEC displayed ≥3 -fold difference (***P<0.0001) in radiation damage in the +RGD:AuNP/+IR compared to the controls. More to it, the sub-millimeter accuracy of image guided radiation therapy facilitated improved therapeutic efficacy (95%-100% tumor dose distribution) and less off-target toxicities. Quantification of the DNA-strand breaks (by γH2AX) showed ≈3 -fold increase (P<0.001) in the radiation specific DNA damage in the 'nanoparticle-radiation' cohort (+RGD:AuNP/+IR: 57%) compared to the 'radiation' group (−RGD:AuNP/+IR:19%) and almost ≈10 -fold difference (P<0.001) compared to (+RGD:AuNP/−IR: 6% and −RGD:AuNP/−IR: 6%). Conclusion: This dual-targeting strategy holds great translational potential in radiation oncology. The resulting vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/ nanoparticle toxicity, extending its utility to intransigent/ non-resectable tumors that barely respond to standard therapies. This abstract presents the first in-depth experimental investigation of tumor vascular disruption with nanoparticles, a novel strategy in radiation therapy.
80.
Cormack, RA; Nguyen, PL; D'Amico, AV; Sridhar, S; Makrigiorgos, M
In Situ Radiosensitization of Brachytherapy: Image Guided Planned Biologic Enhancement of Brachytherapy Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. E649, 2016.
@article{cormack2016situ,
title = {In Situ Radiosensitization of Brachytherapy: Image Guided Planned Biologic Enhancement of Brachytherapy},
author = {RA Cormack and PL Nguyen and AV D'Amico and S Sridhar and M Makrigiorgos},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {E649},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.
Materials/Methods
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).
Results
Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.
Conclusion
Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.
Acknowledgment: DOD PC 110722, Mazzone 2012PD164.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.
Materials/Methods
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).
Results
Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.
Conclusion
Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.
Acknowledgment: DOD PC 110722, Mazzone 2012PD164.
In situ radiosensitizer release concurrent with image guided brachytherapy has been proposed as a means to enhance the therapeutic ratio while avoiding toxicity associated with systemic delivery. Drug-eluting implants have been developed that release radio-sensitizer on time scales comparable to the half-life of isotopes used in brachytherapy procedures. This work presents a means of calculating the combined effect of eluter-source configurations and to optimize source positions for maximal biologic effect.
Materials/Methods
The combined effect of implanted drug eluters and radioactive sources was modeled allowing selection of eluter location to optimize biologic effect for a range of parameters. Implant geometries were extracted from treatment plans of 125I permanent prostate implants. Drug concentrations were simulated using a steady-state solution to the diffusion-elimination equation. Radiosensitization was modeled as dependent on drug concentration up to a saturation concentration. Effective dose was used as a metric to optimize eluter locations. The maximal effective dose was calculated for 3 types of implants across parameter space (diffusion-elimination modulus [φb], saturation concentration [csat], number of eluters [ ne]).
Results
Three types of eluter configurations were evaluated: drug-eluting brachytherapy sources, drug-eluting brachytherapy spacers, and planned eluter positioning. The biologic effect of implanted drug eluters was calculated for prostate volumes from 14 cm3 to 45 cm3, φb from .01 mm-1 to 4 mm-1, (csat) from 0.05 to 7.5 times the steady state drug concentration at the surface of the eluter, and ne from 10 to 60 drug eluters. For the region of (φb, csat) space that results in a large fraction of the gland being maximally sensitized (low values of φb and csat), planned eluter locations do not increase the effective dose of the drug-radiation system more than either eluting spacers or sources. In the majority of the remaining (φb, csat) space (large φb and or csat ), planning the location of drug-eluting spacers will result in a greater biologic effect than sources even where sources often produce greater maximal radiosensitization.
Conclusion
Freely positioned drug-eluting implants offer the best means to increase the biologic effect of brachytherapy implants with minimal change in treatment process. Imaging, already in use for guidance of brachytherapy source placement, can be used to guide placement of radiosensitizing implants. A better understanding of in vivo drug distributions will allow brachytherapy planning systems to be adapted to incorporate the effects of in situ drug delivery.
Acknowledgment: DOD PC 110722, Mazzone 2012PD164.
2010
28.
Gultepe, Evin; Reynoso, Francisco J; Jhaveri, Aditi; Kulkarni, Praveen; Nagesha, Dattatri; Ferris, Craig; Harisinghani, Mukesh; Campbell, Robert B; Sridhar, Srinivas
Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution Journal Article
In: Nanomedicine, vol. 5, no. 8, pp. 1173–1182, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{gultepe2010monitoring,
title = {Monitoring of magnetic targeting to tumor vasculature through MRI and biodistribution},
author = {Evin Gultepe and Francisco J Reynoso and Aditi Jhaveri and Praveen Kulkarni and Dattatri Nagesha and Craig Ferris and Mukesh Harisinghani and Robert B Campbell and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Nanomedicine},
volume = {5},
number = {8},
pages = {1173--1182},
publisher = {Future Medicine Ltd London, UK},
abstract = {The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. MR and biodistribution analysis clearly show the ef?cacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The development of noninvasive imaging techniques for the assessment of cancer treatment is rapidly becoming highly important. The aim of the present study is to show that magnetic cationic liposomes (MCLs), incorporating superparamagnetic iron oxide nanoparticles (SPIONs), are a versatile theranostic nanoplatform for enhanced drug delivery and monitoring of cancer treatment. We have shown that tumor signal intensities in T2-weighted MR images decreased by an average of 20 ± 5% and T2* relaxation times decreased by 14 ± 7 ms 24 h after intravenous administration of our MCL formulation. This compares to an average decrease in tumor signal intensity of 57 ± 12% and a T2* relaxation time decrease of 27 ± 8 ms after the same time period with the aid of magnetic guidance. MR and biodistribution analysis clearly show the ef?cacy of MCLs as MRI contrast agents, prove the use of magnetic guidance, and demonstrate the potential of MCLs as agents for imaging, guidance and therapeutic delivery.
27.
Makrigiorgos, M; Sridhar, S; D’Amico, A; Nguyen, P; Cormack, R
40 poster: Biological In-Situ Dose Painting for IGRT (BIS-IGRT) by Use of Drug-Loaded Implantable Fiducials and Spacers Journal Article
In: Radiotherapy and Oncology, vol. 94, pp. S18, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{makrigiorgos201040,
title = {40 poster: Biological In-Situ Dose Painting for IGRT (BIS-IGRT) by Use of Drug-Loaded Implantable Fiducials and Spacers},
author = {M Makrigiorgos and S Sridhar and A D’Amico and P Nguyen and R Cormack},
year = {2010},
date = {2010-01-01},
journal = {Radiotherapy and Oncology},
volume = {94},
pages = {S18},
publisher = {Elsevier},
abstract = {Conclusions: 18F-ML-10 holds promise for early detection of tumor response to radiation. Generating" Delta image" for mapping response is feasible, and these images may potentially be employed for planning a non-uniform dose administration and adjustment, conforming to differential radio-sensitivity of various regions within the tumor. Multi-center studies are ongoing to evaluate performance of 18F-ML-10 in predicting response of different tumors to radiation.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Conclusions: 18F-ML-10 holds promise for early detection of tumor response to radiation. Generating" Delta image" for mapping response is feasible, and these images may potentially be employed for planning a non-uniform dose administration and adjustment, conforming to differential radio-sensitivity of various regions within the tumor. Multi-center studies are ongoing to evaluate performance of 18F-ML-10 in predicting response of different tumors to radiation.
26.
Gultepe, Evin; Nagesha, Dattatri; Casse, Bernard DF; Banyal, Ravinder; Fitchorov, Trifon; Karma, Alain; Amiji, Mansoor; Sridhar, Srinivas
Sustained Drug Release from Non-eroding Nanoporous Templates Journal Article
In: Small, vol. 6, no. 2, pp. 213–216, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{gultepe2010sustained,
title = {Sustained Drug Release from Non-eroding Nanoporous Templates},
author = {Evin Gultepe and Dattatri Nagesha and Bernard DF Casse and Ravinder Banyal and Trifon Fitchorov and Alain Karma and Mansoor Amiji and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Small},
volume = {6},
number = {2},
pages = {213--216},
publisher = {WILEY-VCH Verlag Weinheim},
abstract = {We present the results for the release of a model drug, doxorubicin (Dox), fromdifferent non-eroding nanopor- ous coatings. Detailed studies of drug release from these platforms in the form of anodic aluminum oxide (AAO) and anodic titaniumoxide (ATO)were carried out. We show that nanoporous surfaces can achieve a sustained release rate over periods of several weeks, similar to polymeric platforms but without the risk of delamination or leaching since they are not degradable. We show that the kinetics of the sustained release from these nanoporous platforms is well described by an activated surface-density-dependent desorptionmodel,which appears to be universal for non-eroding platforms.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
We present the results for the release of a model drug, doxorubicin (Dox), fromdifferent non-eroding nanopor- ous coatings. Detailed studies of drug release from these platforms in the form of anodic aluminum oxide (AAO) and anodic titaniumoxide (ATO)were carried out. We show that nanoporous surfaces can achieve a sustained release rate over periods of several weeks, similar to polymeric platforms but without the risk of delamination or leaching since they are not degradable. We show that the kinetics of the sustained release from these nanoporous platforms is well described by an activated surface-density-dependent desorptionmodel,which appears to be universal for non-eroding platforms.
25.
Nagesha, DK; Tada, DB; Stambaugh, CKK; Gultepe, E; Jost, E; Levy, CO; Cormack, R; Makrigiorgos, GM; Sridhar, S
Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT) Journal Article
In: Physics in Medicine & Biology, vol. 55, no. 20, pp. 6039, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{nagesha2010radiosensitizer,
title = {Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT)},
author = {DK Nagesha and DB Tada and CKK Stambaugh and E Gultepe and E Jost and CO Levy and R Cormack and GM Makrigiorgos and S Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Physics in Medicine & Biology},
volume = {55},
number = {20},
pages = {6039},
publisher = {IOP Publishing},
abstract = {The therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs) . In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer Poly(methyl methacrylate) (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The therapeutic efficiency of IGRT can be further enhanced by biological in-situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs) . In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer Poly(methyl methacrylate) (PMMA) coating and (ii) Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer.
24.
Tada, Dayane B; Singh, Surinder; Nagesha, Dattatri; Jost, Evan; Levy, Craig O; Gultepe, Evin; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Chitosan film containing poly (D, L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release Journal Article
In: Pharmaceutical research, vol. 27, no. 8, pp. 1738–1745, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{tada2010chitosan,
title = {Chitosan film containing poly (D, L-lactic-co-glycolic acid) nanoparticles: a platform for localized dual-drug release},
author = {Dayane B Tada and Surinder Singh and Dattatri Nagesha and Evan Jost and Craig O Levy and Evin Gultepe and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2010},
date = {2010-01-01},
journal = {Pharmaceutical research},
volume = {27},
number = {8},
pages = {1738--1745},
publisher = {Springer US},
abstract = {The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.
Purpose
To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.
Methods
Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).
Results
Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.
Conclusions
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.
Purpose
To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.
Methods
Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).
Results
Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.
Conclusions
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.
Purpose
To characterize and evaluate chitosan film containing PLGA nanoparticles (NPs) as a platform for localized dual-drug release.
Methods
Fluorescent Paclitaxel (FPTX), a hydrophobic drug, was incorporated into PLGA NPs. FPTX-loaded PLGA NPs and Carboxyfluorescein (CF), a hydrophilic model drug, were embedded into chitosan films. Release of CF and NPs from chitosan and release of FPTX from PLGA NPs were monitored by fluorescence. The stability of the platform was observed through SEM and dynamic light scattering (DLS).
Results
Chitosan films containing CF and FPTX-loaded PLGA NPs showed a biphasic release profile. In the first phase, 78% of CF and 34% of NPs were released within few days. In the second phase, the release was slower, showing an additional release of 22% of CF and 18% of NPs after 3 weeks. SEM images and DLS measurements showed that NP release depends on film degradation rate. FPTX-loaded PLGA NPs showed the release of 19.8% of total drug in 2 days, and no additional release was detected in the next 26 days.
Conclusions
The ability of chitosan film containing PLGA NPs to coat gold surface and to incorporate and release two different drugs of different hydrophilicity make it a promising platform for localized dual-drug release.
23.
Cormack, Robert A; Sridhar, Srinivas; Suh, Warren W; D'Amico, Anthony V; Makrigiorgos, Mike G
Biological in situ dose painting for image-guided radiation therapy using drug-loaded implantable devices Journal Article
In: International Journal of Radiation Oncology* Biology* Physics, vol. 76, no. 2, pp. 615–623, 2010.
Abstract | BibTeX | Tags: Nanomedicine
@article{cormack2010biological,
title = {Biological in situ dose painting for image-guided radiation therapy using drug-loaded implantable devices},
author = {Robert A Cormack and Srinivas Sridhar and Warren W Suh and Anthony V D'Amico and Mike G Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {76},
number = {2},
pages = {615--623},
publisher = {Elsevier},
abstract = {Implantable devices routinely used for increasing spatial accuracy in modern image-guided radiation treatments (IGRT), such as fiducials or brachytherapy spacers, encompass the potential for in situ release of biologically active drugs, providing an opportunity to enhance the therapeutic ratio.We model this new approach for two types of treatment. Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug prop- erties were tabulated. Four radiosensitizer-loaded fiducials provide adequate radiosensitization for 4-cm-diameter lung tumors, thus potentially boosting biologically equivalent doses in centrally located stereotactic body treated lesions. Similarly, multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of biologi- cally equivalent doses to fit requirements difficult to meet by using radiation alone, e.g., boosting a high-risk region juxtaposed to the urethra while respecting normal tissue tolerance of both the urethra and the rectum. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Implantable devices routinely used for increasing spatial accuracy in modern image-guided radiation treatments (IGRT), such as fiducials or brachytherapy spacers, encompass the potential for in situ release of biologically active drugs, providing an opportunity to enhance the therapeutic ratio.We model this new approach for two types of treatment. Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug prop- erties were tabulated. Four radiosensitizer-loaded fiducials provide adequate radiosensitization for 4-cm-diameter lung tumors, thus potentially boosting biologically equivalent doses in centrally located stereotactic body treated lesions. Similarly, multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of biologi- cally equivalent doses to fit requirements difficult to meet by using radiation alone, e.g., boosting a high-risk region juxtaposed to the urethra while respecting normal tissue tolerance of both the urethra and the rectum. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
22.
Cormack, R; Nguyen, P; Amico, A D”; Sridhar, S; Makrigiorgos, M
MO-FF-A1-01: Optimal Schedule for Localized Radio-Sensitization of 125I Prostate Implants Journal Article
In: Medical Physics, vol. 37, no. 6Part26, pp. 3361–3361, 2010.
BibTeX | Tags: Nanomedicine
@article{cormack2010mo,
title = {MO-FF-A1-01: Optimal Schedule for Localized Radio-Sensitization of 125I Prostate Implants},
author = {R Cormack and P Nguyen and A D” Amico and S Sridhar and M Makrigiorgos},
year = {2010},
date = {2010-01-01},
journal = {Medical Physics},
volume = {37},
number = {6Part26},
pages = {3361--3361},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
2009
21.
Nagesha, Dattatri K; Plouffe, Brian D; Phan, Minh; Lewis, Laura H; Sridhar, Srinivas; Murthy, Shashi K
Functionalization-induced improvement in magnetic properties of Fe 3 O 4 nanoparticles for biomedical applications Journal Article
In: Journal of Applied Physics, vol. 105, no. 7, pp. 07B317, 2009.
BibTeX | Tags: Nanomedicine
@article{nagesha2009functionalization,
title = {Functionalization-induced improvement in magnetic properties of Fe 3 O 4 nanoparticles for biomedical applications},
author = {Dattatri K Nagesha and Brian D Plouffe and Minh Phan and Laura H Lewis and Srinivas Sridhar and Shashi K Murthy},
year = {2009},
date = {2009-01-01},
journal = {Journal of Applied Physics},
volume = {105},
number = {7},
pages = {07B317},
publisher = {American Institute of Physics},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
20.
Sawant, Rishikesh M; Sawant, Rupa R; Gultepe, Evin; Nagesha, Dattatri; Papahadjopoulos-Sternberg, Brigitte; Sridhar, Srinivas; Torchilin, Vladimir P
Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles Journal Article
In: Journal of Nanoparticle Research, vol. 11, no. 7, pp. 1777, 2009.
Abstract | BibTeX | Tags: Nanomedicine
@article{sawant2009nanosized,
title = {Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles},
author = {Rishikesh M Sawant and Rupa R Sawant and Evin Gultepe and Dattatri Nagesha and Brigitte Papahadjopoulos-Sternberg and Srinivas Sridhar and Vladimir P Torchilin},
year = {2009},
date = {2009-01-01},
journal = {Journal of Nanoparticle Research},
volume = {11},
number = {7},
pages = {1777},
publisher = {Springer Netherlands},
abstract = {Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to ‘plain’ SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.
19.
Sridhar, S
Nanoplatforms for Nanomedicine Journal Article
In: 2009.
Abstract | BibTeX | Tags: Nanomedicine
@article{sridhar2009nanoplatforms,
title = {Nanoplatforms for Nanomedicine},
author = {S Sridhar},
year = {2009},
date = {2009-01-01},
abstract = {Biocompatible nanomaterials are key components of novel approaches to addressing the major problems of modern medicine. A variety of nanoplatforms have emerged that have resulted in dramatic developments in imaging, early diagnosis and targeted delivery of therapeutics. Several varieties of nanoplatforms: metal, semiconducting polymeric and magnetic nanoparticles, liposomes, micelles, and nanoassemblies, have been developed that can enable efficacious delivery of drugs, DNA or energy to localized sites such as tumors, using targeting agents such as antibodies or guided navigation using magnetic fields. The optical properties of these nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications. Magnetic nanoplatforms for theranostics combine multiple functionalities including imaging, magnetic guidance to the disease site, delivery of the drug payload through sustained as well as triggered drug release. Nanoporous coatings have been developed for implants, cardiovascular stents and fiducials used in image guided radio therapy. The non-erodable coatings show sustained release profiles that are comparable to those from erodible polymer platforms, but without the problems of delamination. A new doctoral program has also been established incorporating new courses and interdisciplinary research in nanomedicine.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Biocompatible nanomaterials are key components of novel approaches to addressing the major problems of modern medicine. A variety of nanoplatforms have emerged that have resulted in dramatic developments in imaging, early diagnosis and targeted delivery of therapeutics. Several varieties of nanoplatforms: metal, semiconducting polymeric and magnetic nanoparticles, liposomes, micelles, and nanoassemblies, have been developed that can enable efficacious delivery of drugs, DNA or energy to localized sites such as tumors, using targeting agents such as antibodies or guided navigation using magnetic fields. The optical properties of these nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications. Magnetic nanoplatforms for theranostics combine multiple functionalities including imaging, magnetic guidance to the disease site, delivery of the drug payload through sustained as well as triggered drug release. Nanoporous coatings have been developed for implants, cardiovascular stents and fiducials used in image guided radio therapy. The non-erodable coatings show sustained release profiles that are comparable to those from erodible polymer platforms, but without the problems of delamination. A new doctoral program has also been established incorporating new courses and interdisciplinary research in nanomedicine.
18.
Makrigiorgos, M; Sridhar, S; Suh, W; D'Amico, A; Cormack, R
Biological In Situ Dose-painting for Image-guided Radiation Therapy using Drug-loaded Implantable Devices Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 75, no. 3, pp. S711–S712, 2009.
Abstract | BibTeX | Tags: Nanomedicine
@article{makrigiorgos2009biological,
title = {Biological In Situ Dose-painting for Image-guided Radiation Therapy using Drug-loaded Implantable Devices},
author = {M Makrigiorgos and S Sridhar and W Suh and A D'Amico and R Cormack},
year = {2009},
date = {2009-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {75},
number = {3},
pages = {S711--S712},
publisher = {Elsevier},
abstract = {Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug properties were tabulated. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Drug distributions from three-dimensional arrangements of drug eluters versus eluter size and drug properties were tabulated. Drug loading of implantable devices routinely used in IGRT provides new opportunities for therapy modulation via biological in situ dose painting.
Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …
Drug distributions from three-dimensional arrangements of drug-eluters were tabulated versus eluter size (0.5-2 mm) and drug properties (effective diffusion in tissue). Four regularly-spaced taxotere-loaded fiducials may provide a 50% radio-sensitization in 80-100% of the volume of up to 4 cm diameter lung tumors. The 50% increase in therapeutic ratio provides a boost of biologically-equivalent doses in centrally-located SBRT-treated lesions difficult to treat with radiation alone. Similarly, three-dimensionally planned placement of multiple drug-loaded spacers provide prostate brachytherapy with flexible shaping of ‘biologically-equivalent doses’ to fit requirements that are difficult to meet by using radiation alone, eg boosting biologically-effective dose by 25-50% to a 5 mm high-risk region juxtaposed to the urethra, while respecting the normal tissue tolerance of both urethra and rectum. Further, it is …
17.
Cormack, RA; Sridhar, S; Nagesha, D; Gultepe, E; Suh, W; D'Amico, AV; Makrigiorgos, M
TH-D-210A-06: Drug Eluting Implanted Devices to Increase Biologic Effective Dose in Image Guided Radiation Therapy Journal Article
In: Medical Physics, vol. 36, no. 6Part28, pp. 2819–2819, 2009.
BibTeX | Tags: Nanomedicine
@article{cormack2009th,
title = {TH-D-210A-06: Drug Eluting Implanted Devices to Increase Biologic Effective Dose in Image Guided Radiation Therapy},
author = {RA Cormack and S Sridhar and D Nagesha and E Gultepe and W Suh and AV D'Amico and M Makrigiorgos},
year = {2009},
date = {2009-01-01},
journal = {Medical Physics},
volume = {36},
number = {6Part28},
pages = {2819--2819},
publisher = {American Association of Physicists in Medicine},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
16.
Patel, Yogesh; Saha, Sucharita; DiMarzio, Charles; O'Malley, D; Nagesha, Dattatri; Sridhar, Srinivas
Metallic nanoparticles for biomedical imaging Proceedings Article
In: 2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro, pp. 759–762, IEEE 2009.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{patel2009metallic,
title = {Metallic nanoparticles for biomedical imaging},
author = {Yogesh Patel and Sucharita Saha and Charles DiMarzio and D O'Malley and Dattatri Nagesha and Srinivas Sridhar},
year = {2009},
date = {2009-01-01},
booktitle = {2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro},
pages = {759--762},
organization = {IEEE},
abstract = {The plasmon resonance conditions in nano-sized materials leads to local field enhancement resulting in amplified response of various linear and nonlinear optical processes at the nano-scale. In this paper, metallic nanoparticles are imaged using several modalities – brightfield, confocal reflectance, two-photon, and second harmonic generation. Two examples are discussed . Au nanoparticles in the zebrafish spinal column, and Ag nanoparticles in fresh skin excisions. We show that the optical properties of noble-metal nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
The plasmon resonance conditions in nano-sized materials leads to local field enhancement resulting in amplified response of various linear and nonlinear optical processes at the nano-scale. In this paper, metallic nanoparticles are imaged using several modalities – brightfield, confocal reflectance, two-photon, and second harmonic generation. Two examples are discussed . Au nanoparticles in the zebrafish spinal column, and Ag nanoparticles in fresh skin excisions. We show that the optical properties of noble-metal nanoparticles offer an attractive alternative to the fluorophore-based staining and labeling of biological samples, and have potential use in a wide range of biological and physical applications.
2008
15.
Menon, L; Lu, W; Friedman, A; Bennett, S; Heiman, D; Sridhar, S
Negative Index Metamaterials Based on Metal Nanowire Arrays Electrodeposited in Nanoporous Alumina Templates Journal Article
In: 2008.
Abstract | BibTeX | Tags: Nanomedicine
@article{menonnegative,
title = {Negative Index Metamaterials Based on Metal Nanowire Arrays Electrodeposited in Nanoporous Alumina Templates},
author = {L Menon and W Lu and A Friedman and S Bennett and D Heiman and S Sridhar},
year = {2008},
date = {2008-09-25},
abstract = {Negative index metamaterials are demonstrated based on metal-dielectric nanocomposites. The nanocomposites are prepared using a versatile bottom-up nanofabrication approach involving the incorporation of vertically aligned metal nanowires such as Au and Ag inside dielectric aluminum oxide nanotemplates. Aluminum oxide nanotemplates with specific pore dimensions are fabricated by means of electrochemical anodization. Following this, Au/Ag nanowires with specific wire dimensions are electrodeposited inside the pores. Optical absorbance measurements show resonance peaks corresponding to transverse and longitudinal surface plasmon modes. Peak position and intensity are found to be strongly dependent on nanocomposite dimensions, filling factor (ratio of the volume of metal versus the volume of dielectric) and angle of incidence with respect to the wire axis. A quantitative model based on …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Negative index metamaterials are demonstrated based on metal-dielectric nanocomposites. The nanocomposites are prepared using a versatile bottom-up nanofabrication approach involving the incorporation of vertically aligned metal nanowires such as Au and Ag inside dielectric aluminum oxide nanotemplates. Aluminum oxide nanotemplates with specific pore dimensions are fabricated by means of electrochemical anodization. Following this, Au/Ag nanowires with specific wire dimensions are electrodeposited inside the pores. Optical absorbance measurements show resonance peaks corresponding to transverse and longitudinal surface plasmon modes. Peak position and intensity are found to be strongly dependent on nanocomposite dimensions, filling factor (ratio of the volume of metal versus the volume of dielectric) and angle of incidence with respect to the wire axis. A quantitative model based on …
14.
Nagesha, Dattatri; Devalapally, Harikrishna; Sridhar, Srinivas; Amiji, Mansoor M
Multifunctional magnetic nanosystems for tumor imaging, targeted delivery, and thermal medicine Book Section
In: Multifunctional Pharmaceutical Nanocarriers, pp. 381–408, Springer, New York, NY, 2008.
Abstract | BibTeX | Tags: Nanomedicine
@incollection{nagesha2008multifunctional,
title = {Multifunctional magnetic nanosystems for tumor imaging, targeted delivery, and thermal medicine},
author = {Dattatri Nagesha and Harikrishna Devalapally and Srinivas Sridhar and Mansoor M Amiji},
year = {2008},
date = {2008-01-01},
booktitle = {Multifunctional Pharmaceutical Nanocarriers},
pages = {381--408},
publisher = {Springer, New York, NY},
abstract = {We show that a binary-staircase optical element can be engineered to exhibit an effective negative index of refraction, thereby expanding the range of optical properties theoretically available for future optoelectronic devices. The mechanism for achieving a negative-index lens is based on exploiting the periodicity of the surface corrugation. By designing and nanofabricating a planoconcave binary-staircase lens in the InP∕InGaAsP platform, we have experimentally demonstrated at 1.55μm that such negative-index concave lenses can focus plane waves. The beam propagation in the lens was studied experimentally and was in excellent agreement with the three-dimensional finite-difference time-domain numerical simulations.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {incollection}
}
We show that a binary-staircase optical element can be engineered to exhibit an effective negative index of refraction, thereby expanding the range of optical properties theoretically available for future optoelectronic devices. The mechanism for achieving a negative-index lens is based on exploiting the periodicity of the surface corrugation. By designing and nanofabricating a planoconcave binary-staircase lens in the InP∕InGaAsP platform, we have experimentally demonstrated at 1.55μm that such negative-index concave lenses can focus plane waves. The beam propagation in the lens was studied experimentally and was in excellent agreement with the three-dimensional finite-difference time-domain numerical simulations.
2007
13.
Nagesha, D; Laevsky, GS; Lampton, P; Banyal, R; Warner, C; DiMarzio, C; Sridhar, S
In vitro imaging of embryonic stem cells using multiphoton luminescence of gold nanoparticles Journal Article
In: International journal of nanomedicine, vol. 2, no. 4, pp. 813, 2007.
Abstract | BibTeX | Tags: Nanomedicine
@article{nagesha2007vitro,
title = {In vitro imaging of embryonic stem cells using multiphoton luminescence of gold nanoparticles},
author = {D Nagesha and GS Laevsky and P Lampton and R Banyal and C Warner and C DiMarzio and S Sridhar},
year = {2007},
date = {2007-01-01},
journal = {International journal of nanomedicine},
volume = {2},
number = {4},
pages = {813},
publisher = {Dove Press},
abstract = {Recent advances in nonlinear optical techniques and materials such as quantum wells, nanowires and noble-metal nanoparticles has led to advances in cellular imaging wherein various nanoparticles have been shown to improve both in vitro and in vivo visualization. In this paper, we demonstrate in vitro imaging using multi-photon photoluminescence of gold nanoparticles from two different cell types – Dictyostelium discoideum and mouse embryonic stem cells. By observing nanoparticles we show that embryonic stem cells maintained their ability to proliferate for several passages while grown in the presence of gold nanoparticles. The advantages of multi-photon luminescence using gold nanoparticles have important implications for use in stem cell proliferation experiments and in vitro experiments to monitor differentiation.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Recent advances in nonlinear optical techniques and materials such as quantum wells, nanowires and noble-metal nanoparticles has led to advances in cellular imaging wherein various nanoparticles have been shown to improve both in vitro and in vivo visualization. In this paper, we demonstrate in vitro imaging using multi-photon photoluminescence of gold nanoparticles from two different cell types – Dictyostelium discoideum and mouse embryonic stem cells. By observing nanoparticles we show that embryonic stem cells maintained their ability to proliferate for several passages while grown in the presence of gold nanoparticles. The advantages of multi-photon luminescence using gold nanoparticles have important implications for use in stem cell proliferation experiments and in vitro experiments to monitor differentiation.
12.
Gultepe, E; Nagesha, D; Fantasia, C; Lloyd, S; Tai, S; Sridhar, S
Applications of Nanotemplates and Nanoparticles in Nanomanufacturing and Nanomedicine Journal Article
In: Bulletin of the American Physical Society, vol. 52, 2007.
Abstract | BibTeX | Tags: Nanomedicine
@article{gultepe2007applications,
title = {Applications of Nanotemplates and Nanoparticles in Nanomanufacturing and Nanomedicine},
author = {E Gultepe and D Nagesha and C Fantasia and S Lloyd and S Tai and S Sridhar},
year = {2007},
date = {2007-01-01},
journal = {Bulletin of the American Physical Society},
volume = {52},
publisher = {American Physical Society},
abstract = {Nanotemplates and nanoparticles have potential for use in the area of nanomanufacturing and biomedical applications. Using controlled anodization, nanoporous surface can be achieved on metals such as aluminum and titanium. We are using highly ordered nanoporous alumina as a template for drug delivery and to assemble nanoelements such as latex beads and super coiled DNA by the means of electrophoresis. We have developed a variety of platforms incorporating superparamagnetic iron oxide nanoparticles (SPIONs) for targeted delivery, magnetic hyperthermia and as a contrast agent for magnetic resonance imaging. The results of cell studies on these platforms will be discussed.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Nanotemplates and nanoparticles have potential for use in the area of nanomanufacturing and biomedical applications. Using controlled anodization, nanoporous surface can be achieved on metals such as aluminum and titanium. We are using highly ordered nanoporous alumina as a template for drug delivery and to assemble nanoelements such as latex beads and super coiled DNA by the means of electrophoresis. We have developed a variety of platforms incorporating superparamagnetic iron oxide nanoparticles (SPIONs) for targeted delivery, magnetic hyperthermia and as a contrast agent for magnetic resonance imaging. The results of cell studies on these platforms will be discussed.
2006
11.
Shenoy, Dinesh; Fu, Wei; Li, Jane; Crasto, Curtis; Jones, Graham; DiMarzio, Charles; Sridhar, Srinivas; Amiji, Mansoor
Surface functionalization of gold nanoparticles using hetero-bifunctional poly (ethylene glycol) spacer for intracellular tracking and delivery Journal Article
In: International journal of nanomedicine, vol. 1, no. 1, pp. 51, 2006.
Abstract | BibTeX | Tags: Nanomedicine
@article{shenoy2006surface,
title = {Surface functionalization of gold nanoparticles using hetero-bifunctional poly (ethylene glycol) spacer for intracellular tracking and delivery},
author = {Dinesh Shenoy and Wei Fu and Jane Li and Curtis Crasto and Graham Jones and Charles DiMarzio and Srinivas Sridhar and Mansoor Amiji},
year = {2006},
date = {2006-01-01},
journal = {International journal of nanomedicine},
volume = {1},
number = {1},
pages = {51},
publisher = {Dove Press},
abstract = {For development of surface functionalized gold nanoparticles as cellular probes and delivery agents, we have synthesized hetero-bifunctional poly(ethylene glycol) (PEG, MW 1,500) having a thiol group on one terminus and a reactive functional group on the other for use as a flexible spacer. Coumarin, a model fluorescent dye, was conjugated to one end of the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreases the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within one hour of incubation. Intracellular particle tracking using Keck 3-D Fusion Microscope System shows that the functionalized gold nanoparticles were rapidly internalized in the cells and localized in the peri-nuclear region. Using the PEG spacer, gold nano-platform can be conjugated with a variety of biologically-relevant ligands such as fluorescent dyes, antibodies, etc in order to target, probe, and induce stimulus at the target site.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
For development of surface functionalized gold nanoparticles as cellular probes and delivery agents, we have synthesized hetero-bifunctional poly(ethylene glycol) (PEG, MW 1,500) having a thiol group on one terminus and a reactive functional group on the other for use as a flexible spacer. Coumarin, a model fluorescent dye, was conjugated to one end of the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreases the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within one hour of incubation. Intracellular particle tracking using Keck 3-D Fusion Microscope System shows that the functionalized gold nanoparticles were rapidly internalized in the cells and localized in the peri-nuclear region. Using the PEG spacer, gold nano-platform can be conjugated with a variety of biologically-relevant ligands such as fluorescent dyes, antibodies, etc in order to target, probe, and induce stimulus at the target site.
2005
10.
Li, Jane; Crasto, Curtis F; Weinberg, James S; Amiji, Mansoor; Shenoy, Dinesh; Sridhar, Srinivas; Bubley, Glenn J; Jones, Graham B
An approach to heterobifunctional poly (ethyleneglycol) bioconjugates Journal Article
In: Bioorganic & medicinal chemistry letters, vol. 15, no. 24, pp. 5558–5561, 2005.
Abstract | BibTeX | Tags: Nanomedicine
@article{li2005approach,
title = {An approach to heterobifunctional poly (ethyleneglycol) bioconjugates},
author = {Jane Li and Curtis F Crasto and James S Weinberg and Mansoor Amiji and Dinesh Shenoy and Srinivas Sridhar and Glenn J Bubley and Graham B Jones},
year = {2005},
date = {2005-01-01},
journal = {Bioorganic & medicinal chemistry letters},
volume = {15},
number = {24},
pages = {5558--5561},
publisher = {Elsevier},
abstract = {A family of differentially substituted poly(ethyleneglycol) building blocks has been assembled from commercially available material. Their utility is demonstrated by formation of amino acid conjugates, image contrast agents, gold nanoparticles, and functional antibody conjugates. Application in the cellular trafficking of antitumoral agent conjugates is expected.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
A family of differentially substituted poly(ethyleneglycol) building blocks has been assembled from commercially available material. Their utility is demonstrated by formation of amino acid conjugates, image contrast agents, gold nanoparticles, and functional antibody conjugates. Application in the cellular trafficking of antitumoral agent conjugates is expected.
9.
Fu, W; Shenoy, D; Li, J; Crasto, C; Jones, G; Dimarzio, C; Sridhar, S; Amiji, M
Hetero-bifunctional poly (ethylene glycol) modified gold nanoparticles as an intracellular tracking and delivery agent Proceedings Article
In: NSTI Nanotech, pp. 324–327, 2005.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{fu2005hetero,
title = {Hetero-bifunctional poly (ethylene glycol) modified gold nanoparticles as an intracellular tracking and delivery agent},
author = {W Fu and D Shenoy and J Li and C Crasto and G Jones and C Dimarzio and S Sridhar and M Amiji},
year = {2005},
date = {2005-01-01},
booktitle = {NSTI Nanotech},
volume = {1},
pages = {324--327},
abstract = {To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), hetero-bifunctional poly (ethylene glycol)(PEG), was synthesized having two different functional groups on both the terminals. Coumarin was conjugated to the gold NP through the PEG spacer. The results of cellular cytotoxicity and fluorescence microscopy showed that these NPs were non-toxic and could be internalized in the cells within one hour of incubation.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
To increase the flexibility of surface-attached bio-relevant ligands on gold nanoparticle (NP), hetero-bifunctional poly (ethylene glycol)(PEG), was synthesized having two different functional groups on both the terminals. Coumarin was conjugated to the gold NP through the PEG spacer. The results of cellular cytotoxicity and fluorescence microscopy showed that these NPs were non-toxic and could be internalized in the cells within one hour of incubation.
8.
Saini, G; Shenoy, D; Nagesha, DK; Kautz, R; Sridhar, S; Amiji, M
Superparamagnetic iron oxide-gold core-shell nanoparticles for biomedical applications Proceedings Article
In: 2005 NSTI Nanotechnology Conference and Trade Show-NSTI Nanotech, pp. 328–331, 2005.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{saini2005superparamagnetic,
title = {Superparamagnetic iron oxide-gold core-shell nanoparticles for biomedical applications},
author = {G Saini and D Shenoy and DK Nagesha and R Kautz and S Sridhar and M Amiji},
year = {2005},
date = {2005-01-01},
booktitle = {2005 NSTI Nanotechnology Conference and Trade Show-NSTI Nanotech},
pages = {328--331},
abstract = {Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). We have prepared gold-coated iron oxide nanoparticles that show no change in their superparamagnetic behavior as a consequence of coating. Their potential use as MRI contrast agents was investigated by monitoring their T2 relaxation time with concentration. Cytotoxicity of these nanoparticles was also studied. The results of these studies are presented.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Iron oxide nanoparticles are used for contrast enhancement in magnetic resonance imaging (MRI). We have prepared gold-coated iron oxide nanoparticles that show no change in their superparamagnetic behavior as a consequence of coating. Their potential use as MRI contrast agents was investigated by monitoring their T2 relaxation time with concentration. Cytotoxicity of these nanoparticles was also studied. The results of these studies are presented.
2004
7.
Fu, Wei; Shenoy, Dinesh; Li, Jane; Crasto, Curtis; Jones, Graham; Dimarzio, Charles; Sridhar, Srinivas; Amiji, Mansoor
Biomedical applications of gold nanoparticles functionalized using hetero-bifunctional poly (ethylene glycol) spacer Journal Article
In: MRS Online Proceedings Library Archive, vol. 845, 2004.
Abstract | BibTeX | Tags: Nanomedicine
@article{fu2004biomedical,
title = {Biomedical applications of gold nanoparticles functionalized using hetero-bifunctional poly (ethylene glycol) spacer},
author = {Wei Fu and Dinesh Shenoy and Jane Li and Curtis Crasto and Graham Jones and Charles Dimarzio and Srinivas Sridhar and Mansoor Amiji},
year = {2004},
date = {2004-01-01},
journal = {MRS Online Proceedings Library Archive},
volume = {845},
publisher = {Cambridge University Press},
abstract = {To increase the targeting potential, circulation time, and the flexibility of surface-attached biomedically-relevant ligands on gold nanoparticles, hetero-bifunctional poly(ethylene glycol) (PEG, MW 1, 500) was synthesized having a thiol group on one terminus and a reactive functional group on the other. Coumarin, a model fluorescent dye, was conjugated to the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreases the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within one hour of incubation.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
To increase the targeting potential, circulation time, and the flexibility of surface-attached biomedically-relevant ligands on gold nanoparticles, hetero-bifunctional poly(ethylene glycol) (PEG, MW 1, 500) was synthesized having a thiol group on one terminus and a reactive functional group on the other. Coumarin, a model fluorescent dye, was conjugated to the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreases the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within one hour of incubation.
0000
6.
Nagesha, D; Sawant, R; Parimi, P; Gultepe, E; Bindra, R; Torchilin, V; Sridhar, S
Magnetic nanoparticle vectors: A tool for diagnosis and therapy Journal Article
In: 0000.
Abstract | BibTeX | Tags: Nanomedicine
@article{nageshamagnetic,
title = {Magnetic nanoparticle vectors: A tool for diagnosis and therapy},
author = {D Nagesha and R Sawant and P Parimi and E Gultepe and R Bindra and V Torchilin and S Sridhar},
abstract = {Magnetic nanoparticles (NPs) in the form of iron oxide have been extensively used in nanomedicine for targeted drug delivery, magnetic cell sorting and as a contrast agent for magnetic resonance imaging. We have developed a variety of platforms incorporating magnetic nanoparticles for use in diagnosis and therapy. Iron oxide NPs were encapsulated within micelles, liposomes and polymers to form an enclosed system. In an another system, the surfaces of iron oxide NPs were suitably modified to coat with a thin layer of gold to form an iron oxide-gold core-shell NPs structure. Various biomolecules such as antibodies, fluorescent tags, drugs, plasmid DNA and radioactive labels can be attached to the surface of these magnetic nanoparticles through suitable surface chemistry. Cytotoxicity, cell targeting, cellular uptake and T2 relaxation time were studied for use of these various magnetic NPs-based vectors for …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Magnetic nanoparticles (NPs) in the form of iron oxide have been extensively used in nanomedicine for targeted drug delivery, magnetic cell sorting and as a contrast agent for magnetic resonance imaging. We have developed a variety of platforms incorporating magnetic nanoparticles for use in diagnosis and therapy. Iron oxide NPs were encapsulated within micelles, liposomes and polymers to form an enclosed system. In an another system, the surfaces of iron oxide NPs were suitably modified to coat with a thin layer of gold to form an iron oxide-gold core-shell NPs structure. Various biomolecules such as antibodies, fluorescent tags, drugs, plasmid DNA and radioactive labels can be attached to the surface of these magnetic nanoparticles through suitable surface chemistry. Cytotoxicity, cell targeting, cellular uptake and T2 relaxation time were studied for use of these various magnetic NPs-based vectors for …
5.
Baldwin, Paige; Tangutoori, Shifalika; Sridhar, Srinivas
Nanoformulations of PARP Inhibitors for Cancer Therapy Journal Article
In: 0000.
Abstract | BibTeX | Tags: Nanomedicine
@article{baldwinnanoformulations,
title = {Nanoformulations of PARP Inhibitors for Cancer Therapy},
author = {Paige Baldwin and Shifalika Tangutoori and Srinivas Sridhar},
abstract = {PARP inhibitors (Poly (ADP-ribose) polymerase inhibitors) such as Olaparib are among the most potent molecular inhibitors used in clinical trials for various types of cancers including prostate and ovarian cancers They act by inhibiting DNA damage repair and thus accumulating deleterious mutations leading to genetic instability as a function of number of cell replications. Thus, in this study, we thoroughly characterized and optimized the in vitro model of prostate cancer (PC3, LNCaP, FK01) and ovarian cancer (PA1), in a 96 well system. To compare and contrast the IC-50’s, of free drug and nanoformulated drug, we employed dose response curves generated for each cell line. Prior to this, it was crucial to develop growth rate curves for all cell lines and optimize the seeding density so as to ensure that cell death was not occurring because of over confluence and lack of nutrients, but rather due to the genetic instability caused by the treatment. These curves allow for each cell line to be exposed to the treatment of choice for 4 doubling cycles prior to analysis. Dose response was generated for 4 cell lines, with the 2 different drugs (Olaparib and nano-Olaparib). We determined the IC-50’S of these cells after 4 doubling cycles. These results allowed for comparison between the efficacy of the nanoformulation versus the free drug, thus determining the dose regimen for further invitro studies},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
PARP inhibitors (Poly (ADP-ribose) polymerase inhibitors) such as Olaparib are among the most potent molecular inhibitors used in clinical trials for various types of cancers including prostate and ovarian cancers They act by inhibiting DNA damage repair and thus accumulating deleterious mutations leading to genetic instability as a function of number of cell replications. Thus, in this study, we thoroughly characterized and optimized the in vitro model of prostate cancer (PC3, LNCaP, FK01) and ovarian cancer (PA1), in a 96 well system. To compare and contrast the IC-50’s, of free drug and nanoformulated drug, we employed dose response curves generated for each cell line. Prior to this, it was crucial to develop growth rate curves for all cell lines and optimize the seeding density so as to ensure that cell death was not occurring because of over confluence and lack of nutrients, but rather due to the genetic instability caused by the treatment. These curves allow for each cell line to be exposed to the treatment of choice for 4 doubling cycles prior to analysis. Dose response was generated for 4 cell lines, with the 2 different drugs (Olaparib and nano-Olaparib). We determined the IC-50’S of these cells after 4 doubling cycles. These results allowed for comparison between the efficacy of the nanoformulation versus the free drug, thus determining the dose regimen for further invitro studies
4.
Barlow, Jacob; Gozzi, Kevin; Kelley, Chase; Ven-Moloney, Anne Van De; Chai, Yunrong; Sridhar, Srinivas
Microencapsulation of Bacteria for Controlled Release of Bioactives Journal Article
In: 0000.
BibTeX | Tags: Nanomedicine
@article{barlowmicroencapsulation,
title = {Microencapsulation of Bacteria for Controlled Release of Bioactives},
author = {Jacob Barlow and Kevin Gozzi and Chase Kelley and Anne Van De Ven-Moloney and Yunrong Chai and Srinivas Sridhar},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
3.
Baldwin, Paige; Ohman, Anders; van de Ven, Anne; Dinulescu, Daniela; Sridhar, Srinivas
PARP Inhibitor Nanotherapy for Cancer Treatment Journal Article
In: 0000.
Abstract | BibTeX | Tags: Nanomedicine
@article{baldwinparp,
title = {PARP Inhibitor Nanotherapy for Cancer Treatment},
author = {Paige Baldwin and Anders Ohman and Anne van de Ven and Daniela Dinulescu and Srinivas Sridhar},
abstract = {Poly (ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors, such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways, while leaving healthy cells with multiple repair pathways unharmed. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity. Nanoparticle formulations of Olaparib were developed to allow intravenous (IV) or intraperitoneal (IP) delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities. NanoOlaparib was synthesized and characterized before further testing in vitro and in vivo. In vitro it has been tested in a panel of ovarian cancer cell lines to elucidate sensitivity profiles. NanoOlaparib was also tested in an ovarian cancer IP spread model. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. Radiosensitization with NanoOlaparib was tested in a radiation resistant prostate cancer cell line, FK01 and a xenograft model with the same cells to mimic castration resistant prostate cancer. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib shrinks tumors. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Poly (ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors, such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways, while leaving healthy cells with multiple repair pathways unharmed. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity. Nanoparticle formulations of Olaparib were developed to allow intravenous (IV) or intraperitoneal (IP) delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities. NanoOlaparib was synthesized and characterized before further testing in vitro and in vivo. In vitro it has been tested in a panel of ovarian cancer cell lines to elucidate sensitivity profiles. NanoOlaparib was also tested in an ovarian cancer IP spread model. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. Bioluminescence imaging illustrated that NanoOlaparib administered IP daily resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. Radiosensitization with NanoOlaparib was tested in a radiation resistant prostate cancer cell line, FK01 and a xenograft model with the same cells to mimic castration resistant prostate cancer. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib delays tumor growth, while the combination of radiation and NanoOlaparib shrinks tumors. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP …
2.
Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jhadav, Tej; Fowle, William; Niedre, Mark; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Supporting information Nanoparticles based brachytherapy spacers for delivery of localized combined chemo-radiation therapy Journal Article
In: 0000.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumarsupporting,
title = {Supporting information Nanoparticles based brachytherapy spacers for delivery of localized combined chemo-radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jhadav and William Fowle and Mark Niedre and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
abstract = {Synthesis of NIR fluorescent Silica nanoparticles: The synthesis of conCy7. 5-SNPs was carried out using oil-inwater microemulsion method, following a previously reported protocol with several modifications.(1-2) For conjugating the Cy7. 5 fluorophore in the SNPs, Cy7. 5-NHS ester was first conjugated to a silane precursor using aminopropyltriethoxy silane. 5 mg Cy 7.5 NHS ester (6.4 μmol), 1.77 mg APTES (8 μmol) and 10 μl neat triethylamine were added to 1 ml of anhydrous DMSO and stirred over night at room temperature under Ar atmosphere. The crude mixture was purified using EtOAc-hexane mixture, dried and resuspended in 1ml of DMSO. For synthesizing the Cy7. 5 conjugated ORMOSIL nanoparticles, 10ml of 2.2%(w/v) surfactant AOT solution was prepared in HPLC grade water followed by addition of 600 μl of n-butanol and 50 μl of Cy7. 5-silane under vigorous stirring at rt After 15 min of stirring 100ul of neat VTES was added and resultant reaction mixture was stirred for another 45 minutes. Finally 10ul of NH4OH was added and reaction was allowed to stir overnight. The nanoparticles suspension was then dialyzed against distilled water for 48h at room temperature, using a cellulose membrane with a cut-off size of 12-14 kDa. Following dialysis, the nanoparticles were sterile filtered and stored at 4 C for future use.
Fabrication of INCeRT spacers: For fabricating the spacers, the extracted SNPs from the aqueous mother liquor required a careful assessment, in terms of solvent compatibility with the PLGA polymer, so that both can be dispersed in a single phase without disturbing the integrity of the nanoparticles and the …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Synthesis of NIR fluorescent Silica nanoparticles: The synthesis of conCy7. 5-SNPs was carried out using oil-inwater microemulsion method, following a previously reported protocol with several modifications.(1-2) For conjugating the Cy7. 5 fluorophore in the SNPs, Cy7. 5-NHS ester was first conjugated to a silane precursor using aminopropyltriethoxy silane. 5 mg Cy 7.5 NHS ester (6.4 μmol), 1.77 mg APTES (8 μmol) and 10 μl neat triethylamine were added to 1 ml of anhydrous DMSO and stirred over night at room temperature under Ar atmosphere. The crude mixture was purified using EtOAc-hexane mixture, dried and resuspended in 1ml of DMSO. For synthesizing the Cy7. 5 conjugated ORMOSIL nanoparticles, 10ml of 2.2%(w/v) surfactant AOT solution was prepared in HPLC grade water followed by addition of 600 μl of n-butanol and 50 μl of Cy7. 5-silane under vigorous stirring at rt After 15 min of stirring 100ul of neat VTES was added and resultant reaction mixture was stirred for another 45 minutes. Finally 10ul of NH4OH was added and reaction was allowed to stir overnight. The nanoparticles suspension was then dialyzed against distilled water for 48h at room temperature, using a cellulose membrane with a cut-off size of 12-14 kDa. Following dialysis, the nanoparticles were sterile filtered and stored at 4 C for future use.
Fabrication of INCeRT spacers: For fabricating the spacers, the extracted SNPs from the aqueous mother liquor required a careful assessment, in terms of solvent compatibility with the PLGA polymer, so that both can be dispersed in a single phase without disturbing the integrity of the nanoparticles and the …
Fabrication of INCeRT spacers: For fabricating the spacers, the extracted SNPs from the aqueous mother liquor required a careful assessment, in terms of solvent compatibility with the PLGA polymer, so that both can be dispersed in a single phase without disturbing the integrity of the nanoparticles and the …
1.
Bal, Nandita; Cheng, Ming; Kumar, Rajiv; Sridhar, Srinivas; Ebong, Eno
Increased Nanoparticle Uptake Under Disturbed Flow-Induced Degraded Glycocalyx Conditions Journal Article
In: 0000.
Abstract | BibTeX | Tags: Nanomedicine
@article{balincreased,
title = {Increased Nanoparticle Uptake Under Disturbed Flow-Induced Degraded Glycocalyx Conditions},
author = {Nandita Bal and Ming Cheng and Rajiv Kumar and Srinivas Sridhar and Eno Ebong},
abstract = {Results: The partial LCA ligation model achieved the goal of creating a vessel with disturbed flow and provided a convenient comparison with a healthy RCA experiencing streamlined flow. The vessel walls of the LCA also 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. This was imaged at 10 times magnification (Fig 1) and 63 times magnification (Fig 2).
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 PEG 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. Targeting dysfunctional vessels based on the GCX offers a new approach in cardiovascular disease therapy and prevention.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Results: The partial LCA ligation model achieved the goal of creating a vessel with disturbed flow and provided a convenient comparison with a healthy RCA experiencing streamlined flow. The vessel walls of the LCA also 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. This was imaged at 10 times magnification (Fig 1) and 63 times magnification (Fig 2).
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 PEG 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. Targeting dysfunctional vessels based on the GCX offers a new approach in cardiovascular disease therapy and prevention.
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 PEG 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. Targeting dysfunctional vessels based on the GCX offers a new approach in cardiovascular disease therapy and prevention.
