Publications
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2017
412.
Guthier, Christian V; D'Amico, Anthony V; King, Martin T; Nguyen, Paul L; Orio, Peter F; Sridhar, Srinivas; Makrigiorgos, Mike G; Cormack, Robert A
Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants Journal Article
In: Brachytherapy, vol. 16, no. 3, pp. S115, 2017.
Abstract | BibTeX | Tags: Nanomedicine
@article{guthier2017focal,
title = {Focal Radiosensitization of Brachytherapy: Determining the Optimal Design of Drug Eluting Implants},
author = {Christian V Guthier and Anthony V D'Amico and Martin T King and Paul L Nguyen and Peter F Orio and Srinivas Sridhar and Mike G Makrigiorgos and Robert A Cormack},
year = {2017},
date = {2017-01-01},
journal = {Brachytherapy},
volume = {16},
number = {3},
pages = {S115},
publisher = {Elsevier},
abstract = {In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
In-situ drug release concurrent with radiation therapy has been proposed as a means to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release drugs directly into the prostate. This work models the biologic effect of implantable eluters of radio-sensitizer in conjunction with brachytherapy to determine which of the proposed methods is the preferred delivery approach.
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …
Materials and Methods
The combined effect of implanted drug eluters and radioactive sources were modeled in a manner that allowed selection of eluter location to optimize biologic effect for a range of model parameters. The retrospective study includes 20 patients previously treated with LDR brachytherapy from which prostate geometries, source and spacer positions were extracted. The biological …
411.
van de Ven, Anne L; Tangutoori, Shifalika; Baldwin, Paige; Qiao, Ju; Gharagouzloo, Codi; Seitzer, Nina; Clohessy, John G; Makrigiorgos, Mike G; Cormack, Robert; Pandolfi, Pier Paolo; others,
Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation Journal Article
In: Molecular cancer therapeutics, vol. 16, no. 7, pp. 1279–1289, 2017.
Abstract | BibTeX | Tags: Nanomedicine
@article{van2017nanoformulation,
title = {Nanoformulation of olaparib amplifies PARP inhibition and sensitizes PTEN/TP53-deficient prostate cancer to radiation},
author = {Anne L van de Ven and Shifalika Tangutoori and Paige Baldwin and Ju Qiao and Codi Gharagouzloo and Nina Seitzer and John G Clohessy and Mike G Makrigiorgos and Robert Cormack and Pier Paolo Pandolfi and others},
year = {2017},
date = {2017-01-01},
journal = {Molecular cancer therapeutics},
volume = {16},
number = {7},
pages = {1279--1289},
publisher = {American Association for Cancer Research},
abstract = {The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The use of PARP inhibitors in combination with radiotherapy is a promising strategy to locally enhance DNA damage in tumors. Here we show that radiation-resistant cells and tumors derived from a Pten/Trp53-deficient mouse model of advanced prostate cancer are rendered radiation sensitive following treatment with NanoOlaparib, a lipid-based injectable nanoformulation of olaparib. This enhancement in radiosensitivity is accompanied by radiation dose-dependent changes in γ-H2AX expression and is specific to NanoOlaparib alone. In animals, twice-weekly intravenous administration of NanoOlaparib results in significant tumor growth inhibition, whereas previous studies of oral olaparib as monotherapy have shown no therapeutic efficacy. When NanoOlaparib is administered prior to radiation, a single dose of radiation is sufficient to triple the median mouse survival time compared to radiation only controls. Half of mice treated with NanoOlaparib + radiation achieved a complete response over the 13-week study duration. Using ferumoxytol as a surrogate nanoparticle, MRI studies revealed that NanoOlaparib enhances the intratumoral accumulation of systemically administered nanoparticles. NanoOlaparib-treated tumors showed up to 19-fold higher nanoparticle accumulation compared to untreated and radiation-only controls, suggesting that the in vivo efficacy of NanoOlaparib may be potentiated by its ability to enhance its own accumulation. Together, these data suggest that NanoOlaparib may be a promising new strategy for enhancing the radiosensitivity of radiation-resistant tumors lacking BRCA mutations, such as those with PTEN and TP53 deletions. Mol Cancer Ther; 16(7); 1279–89. ©2017 AACR.
410.
Baldwin, Paige; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas
Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER Miscellaneous
2017.
Abstract | BibTeX | Tags: Nanomedicine
@misc{baldwin2017abstractb,
title = {Abstract NTOC-080: NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER},
author = {Paige Baldwin and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {PURPOSE: PARP inhibitor therapy for ovarian cancer exploits the concept of synthetic lethality by taking advantage of defects in DNA damage repair pathways. Currently Olaparib is the only FDA-approved PARP inhibitor and is available as an oral dosage, which has plenty of advantages, but requires the drug to undergo first pass metabolism, inactivating a significant fraction of the dose. We have developed a nanoparticle delivery system to allow for local delivery of Olaparib directly to the intraperitoneal cavity.
METHODS: NanoOlaparib was characterized in vitro in regards to size, charge, drug loading and release before testing on a panel of ovarian cancer cell lines, including KURAMOCHI, SKOV3, OVSAHO, JHOS2, PA1, COV318, 403 and 404, derived from tumors of Brca2-/-, Pten-/-, Tp53-/- mice, and 4306 and 4412, developed from conditional KrasLSL-G12D/+, Pten-/- mice, to elucidate sensitivity profiles and ensure comparable activity to the free drug. 404 cells, derived from Brca2-/-, Tp53-/-, Pten-/- genetically engineered mouse models, were utilized to develop an IP spread xenograft model to test NanoOlaparib in vivo. Animals were treated with NanoOlaparib or oral Olaparib daily for 4 weeks. Tumor burden was monitored weekly via bioluminescence imaging.
RESULTS: NanoOlaparib shows comparable efficacy in vitro to free Olaparib. The murine cell lines were the most sensitive to the treatment regardless of BRCA status, suggesting that Pten deletions are just as susceptible to PARP inhibitor therapy as the BRCA mutations. The average fold change in bioluminescence for NanoOlaparib decreased, while it increased for oral Olaparib. The oral Olaparib animals had widely varied responses, with some animals' tumors shrinking and others never responding. All NanoOlaparib tumors shrank initially, however, severe toxicity was noted after 3 weeks of treatment.
CONCLUSIONS: NanoOlaparib toxicity in vivo was observed with daily dosing likely due to the sustained release of the drug in comparison to the much more rapid clearance of the oral drug. While the NanoOlaparib was toxic, it provided a much more uniform response to the treatment than the oral Olaparib. It is clear that because this strategy provides 100% of the dose to the disease site with a sustained delivery it is no longer necessary to administer daily. This suggests that NanoOlaparib changes the pharmacokinetics to allow for a lower dose to be administered. A modified dosing regime is to be tested with the goal of lowering the toxicity while still maintaining therapeutic efficacy.
Citation Format: Paige Baldwin, Anders Ohman, Daniela Dinulescu, Srinivas Sridhar. NANOOLAPARIB: AN INTRAPERITONEAL PARP INHIBITOR THERAPY FOR OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-080.
©2017 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
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.
409.
Baldwin, Paige; Kumar, Rajiv; Favours, Edward; Liby, Karen; Kurmasheva, Raushan; Kozono, David; Sridhar, Srinivas
Nanoformulated Talazoparib and Olaparib for enhanced delivery Miscellaneous
2017.
Abstract | BibTeX | Tags: Nanomedicine
@misc{baldwin2017nanoformulated,
title = {Nanoformulated Talazoparib and Olaparib for enhanced delivery},
author = {Paige Baldwin and Rajiv Kumar and Edward Favours and Karen Liby and Raushan Kurmasheva and David Kozono and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: PARP inhibitors such as Talazoparib and Olaparib exploit deficiencies in DNA repair pathways, making them attractive candidates for treatment of a number of different cancers. These drugs are particularly effective when used in combination with other DNA damaging agents such as chemotherapeutics and radiation therapy. Combination trials, however, have resulted in severe toxicities, necessitating either dose reduction or delay. Dose reduction leads to suboptimal dosing and provides little therapeutic benefit compared to monotherapy. Systemically administered nanoparticles offer a more effective way to selectively accumulate drugs in tumors and bypass toxicities associated with oral delivery. We have developed nanoparticle delivery systems for both Olaparib and Talazoparib in order to improve tumor accumulation while bypassing the toxicity associated with oral administration.
Methods: Lipid nanoformulations of Olaparib and Talazoparib have been developed and characterized in regard to size, surface charge, drug loading, release, and stability. NanoTalazoparib has been tested in vitro in breast cancer cell lines including W0069, W780, and HCC1937 which exhibit BRCA1 and 2 mutations, and NanoOlaparib in the lung cancer cell line Calu-6 which also has a defective FA-BRCA pathway. Mice have been treated with NanoOlaparib and NanoTalazoparib alone and in combination with radiation or temozolomide in order to evaluate toxicity. Therapeutic efficacy studies are currently underway.
Results: The nanoformulations have been formulated to encapsulate a clinically relevant dose of either Talazoparib or Olaparib and release at 37°C over a period of days, while remaining stable during storage at 4°C. In vitro, both nanoformulations show the same activity as free drug with IC50s in the nanomolar range for these cell lines with varying deficiencies in the BRCA pathway. Mice have shown no appreciable weight loss during treatment with either nanoformulation alone or in combination with other treatment modalities.
Conclusion: Nanoformulations of Talazoparib and Olaparib have been developed and characterized to demonstrate activity in vitro and tolerable doses in vivo. We have found that mice tolerate NanoTalazoparib at higher doses when combined with Temozolomide than when given oral Talazoparib. The sustained release from the nanoparticles allows for the nanoformulation to be administered less often than the daily administration for oral drug and the improved tolerability opens the door for combination therapy with both chemotherapeutics and radiation therapy. Therapeutic efficacy studies are underway and we expect that as a monotherapy NanoTalazoparib will be more effective at lower doses than oral Talazoparib, based on the longer circulation time and more selective accumulation in tumors. We also anticipate that combination therapy will be more effective with the nanoformulation, as the maximum tolerated dose is higher than that of the oral drug.
Citation Format: Paige Baldwin, Rajiv Kumar, Edward Favours, Karen Liby, Raushan Kurmasheva, David Kozono, Srinivas Sridhar. Nanoformulated Talazoparib and Olaparib for enhanced delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2017-3100
©2017 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
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.
408.
Baig, Nabeela; Likhotvorik, Rostislav; Baldwin, Paige; Sridhar, Srinivas; Kurmasheva, Raushan
Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts Miscellaneous
2017.
Abstract | BibTeX | Tags: Nanomedicine
@misc{baig2017nanoformulation,
title = {Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts},
author = {Nabeela Baig and Rostislav Likhotvorik and Paige Baldwin and Srinivas Sridhar and Raushan Kurmasheva},
year = {2017},
date = {2017-01-01},
publisher = {American Association for Cancer Research},
abstract = {Ewing Family of tumors (EFT) comprises the fourth most common highly malignant childhood cancer. Although sustained event-free survival (EFS) can be achieved with intensive chemo-radiation therapy for patients with local-regional disease, this therapy is relatively ineffective in the treatment of metastatic disease with EFS of 12% at 5 years. Ewing sarcoma is characterized by a reciprocal translocation between chromosomes 11 and 22 that encodes a chimeric oncoprotein resulting from the fusion of EWSR1 to the FLI1 transcription factor in ~85% of tumors. Therapy for patients with EFT comprises surgery, intensive use of cytotoxic agents and radiation therapy. Dose intensification and dose compression has resulted in some improvement in outcome, but patents with advanced or metastatic disease at diagnosis still represent a challenge. Further, patients alive at 5 years from diagnosis still have a high probability of subsequent relapse. Further, long-term consequences of treatment included cardiac dysfunction, and secondary malignancies. Thus, more effective and less toxic therapies are required to treat patients with advanced disease.
Our studies, as part of the Pediatric Preclinical Testing Program (PPTP), identified the combination of the PARP inhibitor, talazoparib, with the DNA damaging agent temozolomide, as being highly synergistic in xenograft models of Ewing sarcoma, but not against other tumor types. In this study 5 of 10 Ewing tumor xenografts models showed dramatic regressions to the combination, while administered as single agents neither talazoparib or temozolomide were active. We have studied the talazoparib-temozolomide synergy in vitro, and results indicate that in models where there is no synergy as xenografts, the cell lines have either intrinsic resistance to talazoparib, temozolomide or both drugs. In mice, and in the clinical trial (NCT02116777), the talazoparib-temozolomide combination is toxic requiring a reduction in temozolomide dose to ~15% of its single maximum-tolerated dose.
We are exploring the use of nanoparticle-formulated talazoparib (npTLZ) developed by Nanomaterials Synthesis Laboratory at Northeastern University without tumor targeting or with antibody-mediated targeting to increase the tumor-drug delivery, reduce normal tissue toxicity (mainly thrombocytopenia), and potentially allow escalation of temozolomide dose. In the PPTP study, the MTD for temozolomide combined with free talazoparib (0.25 mg/kg PO BID daily x 5) was 12 mg/kg. Our recent data showed no toxicity of temozolomide at 66 mg/kg (PO daily x 5) in mice treated with npTLZ (0.5 mg/kg IV daily x 5), suggesting that npTLZ does not potentiate TMZ toxicity to normal mouse tissues. We anticipate that nanoparticle delivery of talazoparib combined with temozolomide will allow reduced toxicity while increasing the response rate for this combination in preclinical models of Ewing sarcoma.
Citation Format: Nabeela Baig, Rostislav Likhotvorik, Paige Baldwin, Srinivas Sridhar, Raushan Kurmasheva. Nanoformulation of talazoparib to increase efficacy when combined with temozolomide for the treatment of Ewing sarcoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5054. doi:10.1158/1538-7445.AM2017-5054
©2017 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
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.
407.
Hachani, Roxanne; Birchall, Martin A; Lowdell, Mark W; Kasparis, Georgios; Tung, Le D; Manshian, Bella B; Soenen, Stefaan J; Gsell, Willy; Himmelreich, Uwe; Gharagouzloo, Codi A; others,
Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging Journal Article
In: Scientific reports, vol. 7, no. 1, pp. 1–14, 2017.
Abstract | BibTeX | Tags: Nanomedicine
@article{hachani2017assessing,
title = {Assessing cell-nanoparticle interactions by high content imaging of biocompatible iron oxide nanoparticles as potential contrast agents for magnetic resonance imaging},
author = {Roxanne Hachani and Martin A Birchall and Mark W Lowdell and Georgios Kasparis and Le D Tung and Bella B Manshian and Stefaan J Soenen and Willy Gsell and Uwe Himmelreich and Codi A Gharagouzloo and others},
year = {2017},
date = {2017-01-01},
journal = {Scientific reports},
volume = {7},
number = {1},
pages = {1--14},
publisher = {Nature Publishing Group},
abstract = {Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging (MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T2 - weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T2-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T2-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
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.
406.
Gharagouzloo, Codi A; Timms, Liam; Qiao, Ju; Fang, Zihang; Nneji, Joseph; Pandya, Aniket; Kulkarni, Praveen; van de Ven, Anne L; Ferris, Craig; Sridhar, Srinivas
Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function Journal Article
In: Neuroimage, vol. 163, pp. 24–33, 2017.
@article{gharagouzloo2017quantitative,
title = {Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function},
author = {Codi A Gharagouzloo and Liam Timms and Ju Qiao and Zihang Fang and Joseph Nneji and Aniket Pandya and Praveen Kulkarni and Anne L van de Ven and Craig Ferris and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Neuroimage},
volume = {163},
pages = {24--33},
publisher = {Academic Press},
abstract = {A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.},
keywords = {MRI},
pubstate = {published},
tppubtype = {article}
}
A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.
405.
Belz, Jodi E; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S; Royce, Darlene B; Zhang, Di; van de Ven, Anne L; Liby, Karen T; Sridhar, Srinivas
Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer Journal Article
In: Theranostics, vol. 7, no. 17, pp. 4340, 2017.
Abstract | BibTeX | Tags: Nanomedicine
@article{belz2017sustained,
title = {Sustained release talazoparib implants for localized treatment of BRCA1-deficient breast cancer},
author = {Jodi E Belz and Rajiv Kumar and Paige Baldwin and Noelle Castilla Ojo and Ana S Leal and Darlene B Royce and Di Zhang and Anne L van de Ven and Karen T Liby and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
journal = {Theranostics},
volume = {7},
number = {17},
pages = {4340},
publisher = {Ivyspring International Publisher},
abstract = {Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
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.
404.
Gharagouzloo, Codi; Sridhar, Srinivas
Quantitative magnetic resonance imaging of the vasculature Miscellaneous
2017.
@misc{gharagouzloo2017quantitativeb,
title = {Quantitative magnetic resonance imaging of the vasculature},
author = {Codi Gharagouzloo and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
abstract = {A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided. The technique can be used to accurately measure contrast agent concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of cerebral blood volume on a voxel -by- voxel basis.},
keywords = {MRI},
pubstate = {published},
tppubtype = {misc}
}
A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided. The technique can be used to accurately measure contrast agent concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of cerebral blood volume on a voxel -by- voxel basis.
403.
Belz, Jodi; Ojo, Noelle Castilla; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne; Liby, Karen; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer Inproceedings
In: CANCER RESEARCH, AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~… 2017.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{belz2017sustainedb,
title = {Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer},
author = {Jodi Belz and Noelle Castilla Ojo and Paige Baldwin and Rajiv Kumar and Anne van de Ven and Karen Liby and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2017},
date = {2017-01-01},
booktitle = {CANCER RESEARCH},
volume = {77},
organization = {AMER ASSOC CANCER RESEARCH 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA~…},
abstract = {Sustained localized delivery of cancer therapeutics is a safe and effective unique option for local control of tumors. Here we report a novel biodegradable implant with the capability to encapsulate different therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ~50μg Talazoparib for BRCA1-mutated breast cancer studies and ~500μg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50's were determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice, W0069 and W780, and human-derived prostate cancer, PC3. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− spontaneous tumored mice for breast cancer studies. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both docetaxel and Talazoparib loading implants. Breast cancer cell lines W0069 and W780 were highly sensitive to Talazoparib, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of Talazoparib, tumors reduced in size by an average of 50%, while untreated tumors increased ~5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Docetaxel implants proved to be an effective method for prostate cancer in vivo with no significant weight loss observed. The local docetaxel spacer group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib and Docetaxel were observed in vitro and in vivo. Therapeutics-loaded implants represent a novel delivery route that are well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of Docetaxel is an effective chemotherapy option alone or in combination with radiation therapy. These results laid a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
This work was supported by the Army- W81XWH-14-1-0092, Breast Cancer Research Foundation and Northeastern University–Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar4. Sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel from modified brachytherapy spacers for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B30.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
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.
402.
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).
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
2016
401.
Sridhar, Srinivas; Petrov, Yury; Yavuzcetin, Ozgur
Electric field encephalography: electric field based brain signal detection and monitoring Miscellaneous
2016, (US Patent App. 14/420,613).
Abstract | BibTeX | Tags: Neurotechnology
@misc{sridhar2016electric,
title = {Electric field encephalography: electric field based brain signal detection and monitoring},
author = {Srinivas Sridhar and Yury Petrov and Ozgur Yavuzcetin},
year = {2016},
date = {2016-03-01},
abstract = {Systems and methods for measuring brain activity of a subject are disclosed, comprising: positioning a plurality of electric field sensors at multiple positions on the exterior of a skull of the subject; measuring one to three components of a plurality of instantaneous electric field vectors generated by a plurality of electric field sources, the electric field vectors being measured by the plurality of electric field sensors; and determining brain activity of the subject based on the measurement of the plurality of instantaneous electric field vectors.},
note = {US Patent App. 14/420,613},
keywords = {Neurotechnology},
pubstate = {published},
tppubtype = {misc}
}
Systems and methods for measuring brain activity of a subject are disclosed, comprising: positioning a plurality of electric field sensors at multiple positions on the exterior of a skull of the subject; measuring one to three components of a plurality of instantaneous electric field vectors generated by a plurality of electric field sources, the electric field vectors being measured by the plurality of electric field sensors; and determining brain activity of the subject based on the measurement of the plurality of instantaneous electric field vectors.
400.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
399.
Baldwin, Paige; Ohman, Anders; Thong, Jeremy; Tangutoori, Shifalika; Dinulescu, Daniela; Sridhar, Srinivas
Abstract A03: PARP inhibitor nanotherapy for ovarian cancer. Miscellaneous
2016.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
398.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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
397.
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.
BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
396.
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).
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
395.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
394.
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.
BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
393.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
392.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
391.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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
390.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
389.
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.
Abstract | BibTeX | Tags: Nanomedicine
@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 = {Nanomedicine},
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.
388.
Baldwin, P; Ven, AL Van De; Seitzer, N; Clohessy, S; Cormack, RA; Makrigiorgos, M; Pandolfi, PP; Sridhar, S
Nanoformulation of the PARP inhibitor olaparib enables radiosensitization of a radiation-resistant prostate cancer model Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. E595, 2016.
Abstract | BibTeX | Tags: Nanomedicine
@article{baldwin2016nanoformulationb,
title = {Nanoformulation of the PARP inhibitor olaparib enables radiosensitization of a radiation-resistant prostate cancer model},
author = {P Baldwin and AL Van De Ven and N Seitzer and S Clohessy and RA Cormack and M Makrigiorgos and PP Pandolfi and S Sridhar},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {E595},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.
Materials/Methods
Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results
Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.
Conclusion
Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.
Materials/Methods
Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results
Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.
Conclusion
Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.
Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents, such as radiation. We hypothesized that delivery of a PARP inhibitor via a nanoformulation would increase the bioavailability and accumulation of the drug at the tumor site thereby leading to greater radiosensitization. Here we report the development and testing of this novel nanoformulation of Olaparib to allow intravenous delivery.
Materials/Methods
Nanoparticle formulations of Olaparib were synthesized and tested in vitro and in vivo. In vitro experiments include a comparison of free Olaparib and NanoOlaparib in prostate cancer cell line FK01, derived from Ptenpc-/-;Trp53pc-/- mice. FK01 is a highly radio-resistant cell line and provided the ideal model to test the relationship between NanoOlaparib and radiation therapy via clonogenic assays. Radiosensitization with NanoOlaparib in vivo was tested in a xenograft model using FK01 cells to mimic castration resistant prostate cancer. Animals were treated biweekly with NanoOlaparib before and after radiation treatment.
Results
Strong radiosensitization was observed in FK01 cells with NanoOlaparib. As expected, there was little difference between free drug and the nanoformulation in vitro because it is formulated to enhance in vivo delivery. The FK01 xenografts are highly radioresistant with little difference between untreated and radiation only animals. NanoOlaparib alone was shown to delay tumor growth, while the combination of radiation and NanoOlaparib clearly shrank the tumors.
Conclusion
Robust nanoparticle formulations of NanoOlaparib have been successfully demonstrated for in vitro and in vivo studies. These results show that NanoOlaparib can sensitize tumors which are normally highly resistant to radiation therapy to this mode of treatment. This implies a very promising potential for NanoOlaparib in the clinic for the treatment of both radiation sensitive and radiation resistant tumors. This work was supported by the IGERT grant NSF-DGE- 0965843 and the Mazzone Foundation.
387.
Belz, J; Ojo, Castilla N; Kumar, R; Cormack, RA; Makrigiorgos, M; Sridhar, S; D'Amico, AV; Nguyen, PL
Docetaxel-Loaded Brachytherapy Spacers for Combined Chemoradiation Therapy in Prostate Cancer Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. S109, 2016.
Abstract | BibTeX | Tags: Nanomedicine
@article{belz2016docetaxel,
title = {Docetaxel-Loaded Brachytherapy Spacers for Combined Chemoradiation Therapy in Prostate Cancer},
author = {J Belz and Castilla N Ojo and R Kumar and RA Cormack and M Makrigiorgos and S Sridhar and AV D'Amico and PL Nguyen},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {S109},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.
Materials/Methods
Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.
Results
The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.
Conclusion
This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.
Materials/Methods
Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.
Results
The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.
Conclusion
This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.
Combined chemo-radiation therapy (CRT) with Docetaxel (DTX) has been shown in several trials to improve survival in multiple cancers. We have developed an innovative combinatorial treatment strategy of local chemoradiation therapy (LCRT) using a sustained drug delivery platform in the form of a spacer loaded with DTX to locally radio-sensitize the prostate enabling a synergistic cure with the use of lower radiation doses. InCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are biodegradable releasing DTX over many weeks.
Materials/Methods
Biodegradable spacers of 1-2 mm length and 0.8 mm diameter were loaded with ∼500 μg Docetaxel (DTX) per spacer for prostate cancer studies. The spacers were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50s were determined using an MTS assay in PC3 cells. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation. Drug-loaded spacers were injected once intratumorally using an 18G brachytherapy needle. Radiation was given using SARRP at 5 Gy, 10 Gy, and 15 Gy.
Results
The release profile of the drug from the spacer in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for DTX loaded spacers. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty spacers and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with localized DTX spacers compared with 0% in all other treatment groups. As hypothesized, the combined treatment with local DTX spacer and radiation (10 Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice which received no treatment showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but tumor growth continued after day 60. A larger experiment to further this study is ongoing.
Conclusion
This approach provides localized in-situ delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with current systemic delivery of docetaxel. Therapeutic-loaded spacers represent a novel delivery route that is well-tolerated. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. DTX loaded spacers would proffer a new treatment option for substantially enhancing therapeutic ratio and boosting cure rate for the hundreds of thousands of Americans diagnosed with prostate cancer each year. This work was supported by the Army W81XWH-14-1-0092, NSF-DGE 0965843, and HHS 1R25CA174650-02.
386.
Kunjachan, S; Detappe, A; Kumar, R; Sridhar, S; Makrigiorgos, M; Berbeco, RI
Nanoparticle-Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy Journal Article
In: International Journal of Radiation Oncology• Biology• Physics, vol. 96, no. 2, pp. S97, 2016.
Abstract | BibTeX | Tags: Nanomedicine
@article{kunjachan2016nanoparticle,
title = {Nanoparticle-Mediated Tumor Vascular Disruption: A Novel Strategy in Radiation Therapy},
author = {S Kunjachan and A Detappe and R Kumar and S Sridhar and M Makrigiorgos and RI Berbeco},
year = {2016},
date = {2016-01-01},
journal = {International Journal of Radiation Oncology• Biology• Physics},
volume = {96},
number = {2},
pages = {S97},
publisher = {Elsevier},
abstract = {Purpose/Objective(s)
More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.
Materials/Methods
(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.
Results
RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).
Conclusion
For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose/Objective(s)
More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.
Materials/Methods
(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.
Results
RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).
Conclusion
For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.
More than half of all cancer patients receive radiation therapy. Despite recent innovations, clinical delivery of curative radiation dose is severely restricted by proximal healthy tissues. Chemical and biological agents to augment the radiosensitization of cancer cells exhibit high off-target toxicity. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. Subsequent tumor vascular damage considerably improved the therapeutic outcome and subsidized the radiation and/or nanoparticle toxicity. This is a unique concept with clear translational path.
Materials/Methods
(Arg-Gly-Asp)- and (PEG)-functionalized gold nanoparticles (RGD:AuNP) were designed and administered to mice pancreatic tumor xenografts (1.25 mg/mL equiv. Au) and angiogenic tumor blood vessels (expressing integrins) were targeted. In 24 h- post-administration, the mice were subjected to targeted irradiation (IR) to induce tumor vascular disruption.
Results
RGD:AuNP formulation (∼3 nm) is non-toxic and stable for more than 6 months. High-res.-TEM, LIBS/STEM imaging confirmed its preferential tumor endothelial uptake. By specifically targeting the early angiogenic neoendothelium, RGD:AuNP circumvent the dense stromal diffusion pathways that often limit the penetration and permeation of anti-cancer drugs and nanoparticles to the tumor cells - a limitation of current radiosensitization approaches. The sub- mm accuracy of image-guided radiation therapy facilitated increased radio-therapeutic efficacy (95-100% tumor-dose distribution) and less off-target toxicity. More than 2.5-fold differences in the specific tumor vascular damage was observed in +RGD:AuNP/+IR (compared to controls) when assessed by γH2AX, 3D-(confocal) vessel imaging, and IHC analysis. Targeted irradiation at 24 h following RGD:AuNP administration showed significant reduction in the tumor size and improved overall animal survival by >140 days (P< 0.0001, Mantel-Cox test), compared to non-treated IR controls (∼95 days).
Conclusion
For the first time, our study demonstrates a catastrophic in vivo induction of “tumor vascular disruption” using targeted-gold nanoparticles and targeted-irradiation. The study was structured based on current clinical practices optimized for high therapeutic efficacy and minimal patient risk. This strategy may also be extended to other intransigent or non-resectable tumors for which radiation delivery is limited by adjacent organs, augmenting its potential clinical impact.
385.
Reyes, Gino Karlo Lapitan Delos; de Ven, Anne Van; Soheilian, Rasam; Sridhar, Srinivas; Erb, Randall; Fenniri, Hicham
Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the Treatment of Pancreatic Cancer Journal Article
In: 2016.
Abstract | BibTeX | Tags: Nanomedicine
@article{reyes2016advancing,
title = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the Treatment of Pancreatic Cancer},
author = {Gino Karlo Lapitan Delos Reyes and Anne Van de Ven and Rasam Soheilian and Srinivas Sridhar and Randall Erb and Hicham Fenniri},
year = {2016},
date = {2016-01-01},
abstract = {Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the
Treatment of Pancreatic Cancer
Gino Karlo Lapitan Delos Reyes1
, Anne Van de Ven2
, Rasam Soheilian3
, Srinivas Sridhar2
, Randall Erb3
,
Hicham Fenniri2
1
Dept. of Chemical Engineering, 2
Dept. of Physics, 3
Dept. of Mechanical and Industrial Engineering,
Northeastern University, Boston, MA
October 28, 2016
11:45 AM, 105 Shillman Hall
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and
a median survival rate of merely six months following diagnosis1
. State-of-the-art therapies involve
subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side
effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the
cancer phenotype2
. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the
Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)
targeted against the KRAS gene to pancreatic cancer cells and silence the gene.
RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload
to pancreatic cancer cells3
. A defining characteristic and strength of the RNTs as a drug delivery vehicle
is the ability to display various functional groups on their surface during self-assembly, conferring to
them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and
biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness
of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)
and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and
function of using the RNT delivery system.
Methods
In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter
plates according to standard protocols. Groups of cells were then administered the following treatments:
untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are
routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,
functions as a positive control. Post-treatment, the cells were then separated into single cell formations
and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.
Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment
of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the
cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into
replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +
siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The
cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total
mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription
polymerase chain reaction (RT-qPCR).
Results and Discussion
In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated
with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged
siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly
75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using
RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked
siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells
transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS
expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also
comparable to the cells transfected with the Lipofectamine. This result is significant because
Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects
and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective
gene delivery vehicle for the treatment of pancreatic cancer.
Funding Acknowledgements
NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843
NSF CPS-1329649
Northeastern University Chemical Engineering Department
References:
1) P. Michl, T. M. Gress, Gut 2012, 317.
2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.
Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-
7163.MCT-14-0074.
3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.
Am. Chem. Soc. 2001, 123, 3854–3855.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Advancing Bio-Inspired Rosette Nanotubes as a Novel and Effective siRNA Delivery Vehicle for the
Treatment of Pancreatic Cancer
Gino Karlo Lapitan Delos Reyes1
, Anne Van de Ven2
, Rasam Soheilian3
, Srinivas Sridhar2
, Randall Erb3
,
Hicham Fenniri2
1
Dept. of Chemical Engineering, 2
Dept. of Physics, 3
Dept. of Mechanical and Industrial Engineering,
Northeastern University, Boston, MA
October 28, 2016
11:45 AM, 105 Shillman Hall
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and
a median survival rate of merely six months following diagnosis1
. State-of-the-art therapies involve
subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side
effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the
cancer phenotype2
. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the
Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)
targeted against the KRAS gene to pancreatic cancer cells and silence the gene.
RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload
to pancreatic cancer cells3
. A defining characteristic and strength of the RNTs as a drug delivery vehicle
is the ability to display various functional groups on their surface during self-assembly, conferring to
them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and
biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness
of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)
and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and
function of using the RNT delivery system.
Methods
In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter
plates according to standard protocols. Groups of cells were then administered the following treatments:
untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are
routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,
functions as a positive control. Post-treatment, the cells were then separated into single cell formations
and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.
Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment
of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the
cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into
replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +
siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The
cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total
mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription
polymerase chain reaction (RT-qPCR).
Results and Discussion
In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated
with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged
siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly
75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using
RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked
siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells
transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS
expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also
comparable to the cells transfected with the Lipofectamine. This result is significant because
Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects
and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective
gene delivery vehicle for the treatment of pancreatic cancer.
Funding Acknowledgements
NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843
NSF CPS-1329649
Northeastern University Chemical Engineering Department
References:
1) P. Michl, T. M. Gress, Gut 2012, 317.
2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.
Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-
7163.MCT-14-0074.
3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.
Am. Chem. Soc. 2001, 123, 3854–3855.
Treatment of Pancreatic Cancer
Gino Karlo Lapitan Delos Reyes1
, Anne Van de Ven2
, Rasam Soheilian3
, Srinivas Sridhar2
, Randall Erb3
,
Hicham Fenniri2
1
Dept. of Chemical Engineering, 2
Dept. of Physics, 3
Dept. of Mechanical and Industrial Engineering,
Northeastern University, Boston, MA
October 28, 2016
11:45 AM, 105 Shillman Hall
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year survival rate of less than 7% and
a median survival rate of merely six months following diagnosis1
. State-of-the-art therapies involve
subjecting patients to a cocktail of anti-cancer drugs, many of which have a host of undesirable side
effects. Implicated in 95% of PDAC patients is a mutated KRAS gene, which functions to enhance the
cancer phenotype2
. It is demonstrated through this work that Rosette Nanotubes (RNTs), developed in the
Supramolecular Nanomaterials Lab, can effectively deliver therapeutic small interfering RNA (siRNA)
targeted against the KRAS gene to pancreatic cancer cells and silence the gene.
RNTs are a biocompatible and tunable nanocarrier that can effectively carry a therapeutic RNA payload
to pancreatic cancer cells3
. A defining characteristic and strength of the RNTs as a drug delivery vehicle
is the ability to display various functional groups on their surface during self-assembly, conferring to
them tunable physical (stability, dimensions), chemical (surface charge and channel properties), and
biological (targeting peptides, bioactive molecules) properties. This works demonstrates the effectiveness
of RNTs to silence oncogenes in an in vitro PDAC cell model. Using fluorescently tagged siRNA (si555)
and siRNA targeted against the oncogene KRAS, we are able to demonstrate effective delivery and
function of using the RNT delivery system.
Methods
In order to determine the efficiency of delivery, Panc1 pancreatic cancer cells were seeded in microtiter
plates according to standard protocols. Groups of cells were then administered the following treatments:
untreated control, naked si555, K1 + si555, and Lipofectamine + si555. The RNTs used in this study are
routinely synthesized in our laboratory. Lipofectamine, a commercially available transfection reagent,
functions as a positive control. Post-treatment, the cells were then separated into single cell formations
and their total internal fluorescence subsequently analyzed on a benchtop flow cytometer.
Furthermore, the function of the siRNA delivered within the cells was evaluated through the assessment
of the expression of the the KRAS gene. In order to assess the function of the siRNA delivered within the
cells, anti-KRAS siRNA (siKRAS) was purchased (Invitrogen). The Panc1 cells were then separated into
replicate groups and administered the following: untreated control, naked siKRAS, K1 + siKRAS, K3 +
siKRAS, or Lipofectamine + siKRAS. Once again, Lipofectamine was utilized as a positive control. The
cells were incubated with the treatments for 48 hours, followed by cell lysis and harvesting of the total
mRNA. The expression of the KRAS gene was then determined using quantitative reverse transcription
polymerase chain reaction (RT-qPCR).
Results and Discussion
In regards to the in vitro studies, the RNTs functioned significantly more effectively than the cells treated
with naked siRNA or the Lipofectamine-treated cells. For example, the cells treated with naked tagged
siRNA showed a total internal fluorescence, signifying intracellular delivery of the siRNA, that is roughly
75% less than the cells treated with the RNTs (Figure 1A). This clearly illustrates the benefit of using
RNTs as a gene delivery vehicle. The results in Figure 1B illustrated that the cells treated with naked
siRNA exhibited little to no knockdown of the KRAS gene, as reported by RT-qPCR. However, the cells
transfected using the K1 and K3 exhibited a remarkably greater knockdown levels (54% and 55% KRAS
expression, respectively) as compared to the naked siRNA control (96%) sample. These results are also
comparable to the cells transfected with the Lipofectamine. This result is significant because
Lipofectamine, although effective at gene delivery in vitro, is well documented to have cytotoxic effects
and is not viable in vivo. Overall, the results of this work demonstrate that RNTs are a viable and effective
gene delivery vehicle for the treatment of pancreatic cancer.
Funding Acknowledgements
NSF IGERT Nanomedicine Science and Technology program at Northeastern University, NSF/DGE096843
NSF CPS-1329649
Northeastern University Chemical Engineering Department
References:
1) P. Michl, T. M. Gress, Gut 2012, 317.
2) C. V Pecot, S. Y. Wu, S. Bellister, J. Filant, R. Rupaimoole, T. Hisamatsu, R. Bhattacharya, A.
Maharaj, S. Azam, C. Rodriguez-aguayo, et al., Small Mol. Ther. 2014, 13, DOI 10.1158/1535-
7163.MCT-14-0074.
3) H. Fenniri, P. Mathivanan, K. L. Vidale, D. M. Sherman, K. Hallenga, K. V. Wood, J. G. Stowell, J.
Am. Chem. Soc. 2001, 123, 3854–3855.
2015
384.
van de Ven, Anne L; Shann, Mary H; Sridhar, Srinivas
Essential components of a successful doctoral program in nanomedicine Journal Article
In: International journal of nanomedicine, vol. 10, pp. 23, 2015.
Abstract | BibTeX | Tags: Education
@article{van2015essential,
title = {Essential components of a successful doctoral program in nanomedicine},
author = {Anne L van de Ven and Mary H Shann and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International journal of nanomedicine},
volume = {10},
pages = {23},
publisher = {Dove Press},
abstract = {The Nanomedicine program at Northeastern University provides a unique interdisciplinary graduate education that combines experiential research, didactic learning, networking, and outreach. Students are taught how to apply nanoscience and nanotechnology to problems in medicine, translate basic research to the development of marketable products, negotiate ethical and social issues related to nanomedicine, and develop a strong sense of community involvement within a global perspective. Since 2006, the program has recruited 50 doctoral students from ten traditional science, technology, and engineering disciplines to participate in the 2-year specialization program. Each trainee received mentoring from two or more individuals, including faculty members outside the student’s home department and faculty members at other academic institutions, and/or clinicians. Both students and faculty members reported a significant increase in interdisciplinary scholarly activities, including publications, presentations, and funded research proposals, as a direct result of the program. Nearly 90% of students graduating with a specialization in nanomedicine have continued on to careers in the health care sector. Currently, 43% of graduates are performing research or developing products that directly involve nanomedicine. This article identifies some key elements of the Nanomedicine program, describes how they were implemented, and reports on the metrics of success.
Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training},
keywords = {Education},
pubstate = {published},
tppubtype = {article}
}
The Nanomedicine program at Northeastern University provides a unique interdisciplinary graduate education that combines experiential research, didactic learning, networking, and outreach. Students are taught how to apply nanoscience and nanotechnology to problems in medicine, translate basic research to the development of marketable products, negotiate ethical and social issues related to nanomedicine, and develop a strong sense of community involvement within a global perspective. Since 2006, the program has recruited 50 doctoral students from ten traditional science, technology, and engineering disciplines to participate in the 2-year specialization program. Each trainee received mentoring from two or more individuals, including faculty members outside the student’s home department and faculty members at other academic institutions, and/or clinicians. Both students and faculty members reported a significant increase in interdisciplinary scholarly activities, including publications, presentations, and funded research proposals, as a direct result of the program. Nearly 90% of students graduating with a specialization in nanomedicine have continued on to careers in the health care sector. Currently, 43% of graduates are performing research or developing products that directly involve nanomedicine. This article identifies some key elements of the Nanomedicine program, describes how they were implemented, and reports on the metrics of success.
Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training
Keywords: nanomedicine, IGERT, nanotechnology, nanoscience, education, graduate training
383.
Kumar, Rajiv; Belz, Jodi; Markovic, Stacey; Jadhav, Tej; Fowle, William; Niedre, Mark; Cormack, Robert; Makrigiorgos, Mike G; Sridhar, Srinivas
Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy Journal Article
In: International Journal of Radiation Oncology* Biology* Physics, vol. 91, no. 2, pp. 393–400, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{kumar2015nanoparticle,
title = {Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy},
author = {Rajiv Kumar and Jodi Belz and Stacey Markovic and Tej Jadhav and William Fowle and Mark Niedre and Robert Cormack and Mike G Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Radiation Oncology* Biology* Physics},
volume = {91},
number = {2},
pages = {393--400},
publisher = {Elsevier},
abstract = {Purpose
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Purpose
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits.
Methods and Materials
Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues.
Results
The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days.
Conclusions
The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.
382.
Tangutoori, Shifalika; Baldwin, Paige; Sridhar, Srinivas
PARP inhibitors: A new era of targeted therapy Journal Article
In: Maturitas, vol. 81, no. 1, pp. 5–9, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{tangutoori2015parp,
title = {PARP inhibitors: A new era of targeted therapy},
author = {Shifalika Tangutoori and Paige Baldwin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {Maturitas},
volume = {81},
number = {1},
pages = {5--9},
publisher = {Elsevier},
abstract = {Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Personalized medicine seeks to utilize targeted therapies with increased selectivity and efficacy in preselected patient cohorts. One such molecularly targeted therapy is enabled by inhibiting the enzyme poly(ADP-ribose) polymerase (PARP) by small molecule inhibitors in tumors which have a defect in the homologous DNA recombination pathway, most characteristically due to BRCA mutations. Olaparib, a highly potent PARP inhibitor, has recently been the approved for ovarian cancer therapy by the FDA and European commission in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with BRCA1 or BRCA2 mutations. Currently, clinical trials with several PARP inhibitors are being conducted to assess the toxicities, the efficacies and the benefit of the drugs as monotherapies or combined with radiation or other chemotherapeutic agents, in ovarian, breast, prostate, rectal, lung, pancreatic, peritoneal, head and neck, brain, squamous cell carcinomas and sarcomas, to list a few. In this review, our focus is to outline the emerging molecular mechanisms, preclinical evidence and clinical applications of PARP inhibitors especially in nonBRCA cancers, and review the combination strategies compatible with PARP inhibitor therapy.
381.
Cheng, Ming; Homayoni, Homa; Kumar, Rajiv; Sridhar, Srinivas; Webster, Thomas; Ebong, Eno
Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake Journal Article
In: The FASEB Journal, vol. 29, no. 1_supplement, pp. LB168, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{cheng2015endothelial,
title = {Endothelial Glycocalyx Health Plays Critical Role in Nanoparticle Uptake},
author = {Ming Cheng and Homa Homayoni and Rajiv Kumar and Srinivas Sridhar and Thomas Webster and Eno Ebong},
year = {2015},
date = {2015-01-01},
journal = {The FASEB Journal},
volume = {29},
number = {1_supplement},
pages = {LB168},
publisher = {The Federation of American Societies for Experimental Biology},
abstract = {The endothelial cells in the blood vessels are lined with a meshwork of polysaccharides called the glycocalyx (GCX). There is evidence this protective layer is dysfunctional in patients suffering from various diseases including diabetes, atherosclerosis, and metastatic cancer. GCX dysfunction may impair or amplify the effect of drugs delivered to treat disease, and particularly drugs delivered using nanoparticle vehicles that are becoming very popular. However, there is currently no in vitro process of screening nanoparticle-based drug delivery that tests the role of GCX health in delivery of the nanoparticles or drug itself. To address this issue, we are using ultra-small PEGylated gold nanoparticles (NP) to visualize the effects of GCX on nanoparticle uptake by rat fat pad endothelial cells. We are examining the effect of intact GCX. In addition, two types of GCX dysfunction are modeled: degradation due to the addition of heparinase III enzyme that degrades the heparan sulfate component of the glycocalyx, and collapse due to culturing the cells in low serum media. In another model, we induce GCX regeneration through addition of heparan sulfate after heparinase III treatment. The cells are then incubated with nanoparticles overnight, fixed and stained, then imaged through confocal microscopy. Both cell cultures with damaged GCX showed significantly higher NP uptake compared to the cultures with intact or regenerated GCX. This work indicates that the GCX integrity and composition does influence NP uptake for the endothelial cells.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
The endothelial cells in the blood vessels are lined with a meshwork of polysaccharides called the glycocalyx (GCX). There is evidence this protective layer is dysfunctional in patients suffering from various diseases including diabetes, atherosclerosis, and metastatic cancer. GCX dysfunction may impair or amplify the effect of drugs delivered to treat disease, and particularly drugs delivered using nanoparticle vehicles that are becoming very popular. However, there is currently no in vitro process of screening nanoparticle-based drug delivery that tests the role of GCX health in delivery of the nanoparticles or drug itself. To address this issue, we are using ultra-small PEGylated gold nanoparticles (NP) to visualize the effects of GCX on nanoparticle uptake by rat fat pad endothelial cells. We are examining the effect of intact GCX. In addition, two types of GCX dysfunction are modeled: degradation due to the addition of heparinase III enzyme that degrades the heparan sulfate component of the glycocalyx, and collapse due to culturing the cells in low serum media. In another model, we induce GCX regeneration through addition of heparan sulfate after heparinase III treatment. The cells are then incubated with nanoparticles overnight, fixed and stained, then imaged through confocal microscopy. Both cell cultures with damaged GCX showed significantly higher NP uptake compared to the cultures with intact or regenerated GCX. This work indicates that the GCX integrity and composition does influence NP uptake for the endothelial cells.
380.
Cifter, G; Sajo, E; Korideck, H; Kumar, R; Sridhar, S; Cormack, R; Makrigiorgos, G; Ngwa, W
MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles Journal Article
In: Medical physics, vol. 42, no. 6Part29, pp. 3565–3565, 2015.
BibTeX | Tags:
@article{cifter2015mo,
title = {MO-FG-BRA-05: Next Generation Radiotherapy Biomaterials Loaded With Gold Nanoparticles},
author = {G Cifter and E Sajo and H Korideck and R Kumar and S Sridhar and R Cormack and G Makrigiorgos and W Ngwa},
year = {2015},
date = {2015-01-01},
journal = {Medical physics},
volume = {42},
number = {6Part29},
pages = {3565--3565},
publisher = {American Association of Physicists in Medicine},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
379.
Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK
Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration Inproceedings
In: 2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC), pp. 1–2, IEEE 2015.
Abstract | BibTeX | Tags: Nanomedicine
@inproceedings{adedoyin2015injectable,
title = {Injectable bionanocomposite hybrid scaffolds with responsive control for enhanced osteochondral tissue regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {2015 41st Annual Northeast Biomedical Engineering Conference (NEBEC)},
pages = {1--2},
organization = {IEEE},
abstract = {Restoration of articular hyaline cartilage within osteochondral tissue defects has been a principal target in the field of tissue engineering due to poor functional regeneration of this avascular and heterogeneous tissue following current treatment options. The major focus thus far has been in constructing implantable scaffolds, which can be readily designed to offer appropriate mechanical properties. However, the use of implantable scaffolds requires open surgery and often cannot be readily applied to defects of irregular shape. Thus, it has become of high interest to develop minimally invasive and degradable hydrogel-based materials capable of delivering and maintaining encapsulated cells in a non-toxic manner and encouraging functional tissue regeneration. This paper reports on the synthesis and characterization of a novel class of injectable, thermally and chemically dual-gelling bionanocomposite hydrogels from thermogelling macromers (TGMs) based on poly(N-isopropylacrylamide) (pNiPAAm), degradable polyamidoamine (PAMAMs) crosslinking macromers, and functional hybrid inorganic iron oxide (Fe 3 O 4 ) nanoparticles capable of responding to an external magnetic field to stimulate cell activity and control the regenerative process in situ in a spatiotemporal manner.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
Restoration of articular hyaline cartilage within osteochondral tissue defects has been a principal target in the field of tissue engineering due to poor functional regeneration of this avascular and heterogeneous tissue following current treatment options. The major focus thus far has been in constructing implantable scaffolds, which can be readily designed to offer appropriate mechanical properties. However, the use of implantable scaffolds requires open surgery and often cannot be readily applied to defects of irregular shape. Thus, it has become of high interest to develop minimally invasive and degradable hydrogel-based materials capable of delivering and maintaining encapsulated cells in a non-toxic manner and encouraging functional tissue regeneration. This paper reports on the synthesis and characterization of a novel class of injectable, thermally and chemically dual-gelling bionanocomposite hydrogels from thermogelling macromers (TGMs) based on poly(N-isopropylacrylamide) (pNiPAAm), degradable polyamidoamine (PAMAMs) crosslinking macromers, and functional hybrid inorganic iron oxide (Fe 3 O 4 ) nanoparticles capable of responding to an external magnetic field to stimulate cell activity and control the regenerative process in situ in a spatiotemporal manner.
378.
Ozturk, Birol; de-Luna-Bugallo, Andres; Panaitescu, Eugen; Chiaramonti, Ann N; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Kharche, Neerav; Yavuzcetin, Ozgur; Alnaji, Majed; others,
Atomically thin layers of B--N--C--O with tunable composition Journal Article
In: Science advances, vol. 1, no. 6, pp. e1500094, 2015.
BibTeX | Tags:
@article{ozturk2015atomically,
title = {Atomically thin layers of B--N--C--O with tunable composition},
author = {Birol Ozturk and Andres de-Luna-Bugallo and Eugen Panaitescu and Ann N Chiaramonti and Fangze Liu and Anthony Vargas and Xueping Jiang and Neerav Kharche and Ozgur Yavuzcetin and Majed Alnaji and others},
year = {2015},
date = {2015-01-01},
journal = {Science advances},
volume = {1},
number = {6},
pages = {e1500094},
publisher = {American Association for the Advancement of Science},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
377.
Kumar, Rajiv; Belz, Jodi; Korideck, Houari; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2015local,
title = {Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models},
author = {Rajiv Kumar and Jodi Belz and Houari Korideck and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Systemic chemotherapy which is often used in combination with radiation therapy in the treatment of prostate cancer, often leads to severe systemic toxicities. Localized chemotherapy has the potential of delivering a high and effective dose directly to the tumor while minimizing adverse toxicities to healthy tissue. An efficient local delivery system should be able to deliver the therapeutic drug at the diseased site in a slow and sustained manner with minimal systemic toxicity. We have fabricated an Implantable Nanoplatform for Chemo-Radiation Therapy (INCeRT) spacer that can deliver planned, localized, and sustained delivery of a chemotherapeutic and imaging agent. Delivery of this new chemotherapy modality can leverage technology used in a routine clinical brachytherapy procedure that uses image guidance to insert radioactive seeds into the prostate using thin needles. The current procedure uses inert plastic spacers with no therapeutic impact to guide the spatial delivery of the radioactive seeds.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Systemic chemotherapy which is often used in combination with radiation therapy in the treatment of prostate cancer, often leads to severe systemic toxicities. Localized chemotherapy has the potential of delivering a high and effective dose directly to the tumor while minimizing adverse toxicities to healthy tissue. An efficient local delivery system should be able to deliver the therapeutic drug at the diseased site in a slow and sustained manner with minimal systemic toxicity. We have fabricated an Implantable Nanoplatform for Chemo-Radiation Therapy (INCeRT) spacer that can deliver planned, localized, and sustained delivery of a chemotherapeutic and imaging agent. Delivery of this new chemotherapy modality can leverage technology used in a routine clinical brachytherapy procedure that uses image guidance to insert radioactive seeds into the prostate using thin needles. The current procedure uses inert plastic spacers with no therapeutic impact to guide the spatial delivery of the radioactive seeds.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.
This work presents the fabrication, characterization, and therapeutic benefit of a docetaxel loaded spacer in the treatment of prostate-tumored mice. First, INCeRT spacers were fabricated and characterized using optical imaging to track free dye and multi-sized fluorescent silica nanoparticles from spacers in vivo to optimize the temporal and spatial properties of diffusion distribution from a degrading biocompatible polymer matrix. In vivo optical imaging of spacers doped with free dye demonstrates a spatial and temporal release profile appropriate for sustained localized exposure of a chemotherapeutic during the course of brachytherapy. The optimized spacer were loaded with chemotherapeutics and inserted intratumorally for efficacy and toxicity of the localized chemotherapy in comparison to the standard systemic dosing. The in vivo results suggest that local chemotherapy is not only feasible, but as effective as current treatment options. An intratumoral free docetaxel spacer showed to be as effective as a one-time equivalent dose of the clinically used systemic taxotere without the associated adverse toxicities. This new localized chemo-treatment shows great potential for increasing tumor regression while decreasing systemic toxicity. Further experiments for studying the combined chemo-radiation therapy are underway. This demonstrates that local chemotherapy and chemo-radiation therapy has the potential to be a superior treatment option to current chemo-treatments.
This work was supported partially by ARMY/ W81XWH-12-1-0154, NSF-DGE-0965843, HHS/1U54CA151881 CORE1 and a seed grant from the BWH Biomedical Research Institute.
Citation Format: Rajiv Kumar, Jodi Belz, Houari Korideck, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Local chemotherapy and chemoradiation therapy using INCeRT brachytherapy implants in cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1806. doi:10.1158/1538-7445.AM2015-1806
©2015 American Association for Cancer Research.
376.
Tangutoori, Shifalika; Bladwin, Paige; Ohman, Anders; Korideck, Houari; Cormack, Robert; Dinulescu, Daniela; Makrigiorgos, Mike; Sridhar, Srinivas
NanoPARPi inhibitors for ovarian and prostate cancer therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015nanoparpi,
title = {NanoPARPi inhibitors for ovarian and prostate cancer therapy},
author = {Shifalika Tangutoori and Paige Bladwin and Anders Ohman and Houari Korideck and Robert Cormack and Daniela Dinulescu and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly ADP Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) or BMN-673 (200μM) and Cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly ADP Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib and BMN-673 are potent PARP inhibitors that are currently indicated for chronic therapy in several clinical trials for a variety of cancers. Here we report novel and well characterized nanoformulations customized for olaparib (NanoOlaparib) and BMN-673 (NanoBMN-673), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity. Our nanoplatform is also tailored for the combinatorial chemotherapy and radio-sensitization in several cancers including prostate, ovarian and breast cancer cell lines with and without the BRCA mutations.
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) or BMN-673 (200μM) and Cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.
Methods: Two nanoparticle formulations, NanoOlaparib and NanoBMN-673 have been successfully formulated and tested invitro on several cancer cell lines. The initial combination studies were performed with Cisplatin and each of the PARP inhibitors and the nanoformulation is defined by nanoparticles ∼120 nm diameter, zeta potential ∼ +30mV, and loaded with Olaparib (18mM) or BMN-673 (200μM) and Cisplatin (∼3.3mM). Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines were generated using various customized assays and EC50's were determined. The synergism due to radiosensitization was studied for both therapies using isobolograms. The efficacy of combination PARPi and Pt therapy with nanoparticle platform was determined on GEMM models of endometrial cancers. The functionality of nanoPARPi formulations, reflected by inhibition of PARylation, and cleaved PARP was determined by immunoflourescence assays.
Results: NanoPARPi inhibitors were assayed on atleast 8 ovarian cancer cells using various cell based assays. NanoBMN was the most potent PARP inhibitor which is not functionally dependent on BRCA sensitive cells lines whereas nanoOlaparib, seems to be sensitive towards triple negative GEMM derived Ovarian cells (403, 404). PTEN deficient prostate cancer cells were more susceptible to radiosensitization with both nanoPARPi inhibitors (Olaparib, BMN-673), achieving significant long-term cell kill. In all studies NanoBMN-673 showed better efficacy in combination with radiation than NanoOlaparib. In vivo studies with irradiation are underway.
Conclusions: Robust nanoformulations, NanoOlaparib and nanoBMN-673 have been successfully demonstrated. We observed a significant enhancement in the efficacy with both nanoformulations. Strong radiosensitization was observed after several days. These results imply an important role for the nanoOlaparib and nanoBMN-673 as chemo and radio-sensitizers enabling several combination therapeutic approaches.
Citation Format: Shifalika Tangutoori, Paige Bladwin, Anders Ohman, Houari Korideck, Robert Cormack, Daniela Dinulescu, Mike Makrigiorgos, Srinivas Sridhar. NanoPARPi inhibitors for ovarian and prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3670. doi:10.1158/1538-7445.AM2015-3670
©2015 American Association for Cancer Research.
375.
Tangutoori, Shifalika; Baldwin, Paige; Medina, Jamie; Ohman, Anders; Dinulescu, Daniela; Sridhar, Srinivas
Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015abstract,
title = {Abstract AS29: PARP inhibitor nano-therapy in ovarian cancer models},
author = {Shifalika Tangutoori and Paige Baldwin and Jamie Medina and Anders Ohman and Daniela Dinulescu and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Introduction: Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Olaparib is a potent PARP inhibitors that is currently indicated for oral inhibitor therapy in several clinical trials for a variety of cancers. Oral administration of these inhibitors in general results in poor bioavailability and tumor accumulation. Here we report the first novel nanoformulations customized for olaparib (NanoOlaparib), thus enabling a platform which provides a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.
Methods: Two nanoparticle (120nm size) formulations NanoOlaparib and NanoOlaparibPt have been successfully formulated and tested in vitro on several cancer cell lines. Dose response curves over a dynamic range of nanoPARPi therapy on several cell lines PA-1, KURAMOCHI, OVSAHO, SKOV3, and 4306, were generated using MTS assay and EC50's were determined using Prism. The synergism due to chemosensitization using cisplatin was studied for both therapies using isobolograms developed from delayed viability assay.
Results: In vitro studies Cell viability studies were carried out with NanoOlaparib and NanoOlaparibPt in OvCa cell lines. The highly Pt-sensitive cell line PA-1 is strongly responsive to NanoOlaparib (blue) and NanoOlaparibPt (grey) although it is not known to carry a germline BrCa mutation. The multi-drug resistant cell line SKOV-3 is also more responsive to NanoOlaparib and combination NanoOlaparibPt. In vivo studies A pilot study was carried out in an endometrial OvCa murine model with KRaS-PTEN deletion to test the nanoformulations for biocompatibility and therapeutic efficacy. Bioluminescence images (Fig. 2) show tumor suppression of more than a nearly a factor of 3. All formulations were well tolerated.
Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+ Olaparib/DMSO. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with NanoOlaparib when compared to olaparib alone. Increased tumor accumulation and therapeutic efficacy were observed in prostate and breast cancer GEM models. These results show that NanoOlaparib amplifies the therapeutic efficacy of PARP inhibition and imply a very promising role for the nano-olaparib formulation in ovarian and other cancers.
374.
Kunjachan, Sijumon; Detappe, Alexandre; Kumar, Rajiv; Ireland, Thomas; Cameron, Lisa; Biancur, Douglas E; Motto-Ros, Vincent; Sancey, Lucie; Sridhar, Srinivas; Makrigiorgos, Mike G; others,
Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy Journal Article
In: Nano letters, vol. 15, no. 11, pp. 7488–7496, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{kunjachan2015nanoparticle,
title = {Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy},
author = {Sijumon Kunjachan and Alexandre Detappe and Rajiv Kumar and Thomas Ireland and Lisa Cameron and Douglas E Biancur and Vincent Motto-Ros and Lucie Sancey and Srinivas Sridhar and Mike G Makrigiorgos and others},
year = {2015},
date = {2015-01-01},
journal = {Nano letters},
volume = {15},
number = {11},
pages = {7488--7496},
publisher = {American Chemical Society},
abstract = {More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
More than 50% of all cancer patients receive radiation therapy. The clinical delivery of curative radiation dose is strictly restricted by the proximal healthy tissues. We propose a dual-targeting strategy using vessel-targeted-radiosensitizing gold nanoparticles and conformal-image guided radiation therapy to specifically amplify damage in the tumor neoendothelium. The resulting tumor vascular disruption substantially improved the therapeutic outcome and subsidized the radiation/nanoparticle toxicity, extending its utility to intransigent or nonresectable tumors that barely respond to standard therapies.
373.
Adedoyin, AA; Kumar, R; Sridhar, S; Ekenseair, AK
Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration Inproceedings
In: TISSUE ENGINEERING PART A, pp. S307–S307, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{adedoyin2015synthesis,
title = {Synthesis and Characterization of Injectable Bionanocomposite Hybrid Scaffolds with Responsive Control for Osteochondral Tissue Regeneration},
author = {AA Adedoyin and R Kumar and S Sridhar and AK Ekenseair},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S307--S307},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
372.
Cheng, MJ; Kumar, R; Sridhar, S; Webster, TJ; Ebong, EE
Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells Inproceedings
In: TISSUE ENGINEERING PART A, pp. S401–S401, MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{cheng2015glycocalyx,
title = {Glycocalyx Integrity Influences Nanoparticle Uptake by Endothelial Cells},
author = {MJ Cheng and R Kumar and S Sridhar and TJ Webster and EE Ebong},
year = {2015},
date = {2015-01-01},
booktitle = {TISSUE ENGINEERING PART A},
volume = {21},
pages = {S401--S401},
organization = {MARY ANN LIEBERT, INC 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
371.
Ozturk, Birol; Yavuzcetin, Ozgur; Sridhar, Srinivas
A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications Journal Article
In: International Journal of Optics, vol. 2015, 2015.
Abstract | BibTeX | Tags: Nanomedicine, Sensors
@article{ozturk2015novel,
title = {A novel coupled resonator photonic crystal design in lithium niobate for electrooptic applications},
author = {Birol Ozturk and Ozgur Yavuzcetin and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
journal = {International Journal of Optics},
volume = {2015},
publisher = {Hindawi},
abstract = {High-aspect-ratio photonic crystal air-hole fabrication on bulk Lithium Niobate (LN) substrates is extremely difficult due to its inherent resistance to etching, resulting in conical structures and high insertion losses. Here, we propose a novel coupled resonator photonic crystal (CRPC) design, combining a coupled resonator approach with that of Bragg gratings. CRPC design parameters were optimized by analytical calculations and FDTD simulations. CRPC structures with optimized parameters were fabricated and electrooptically tested on bulk LN annealed proton exchange waveguides. Low insertion loss and large electrooptic effect were observed with the fabricated devices, making the CRPC design a promising structure for electrooptic device applications.},
keywords = {Nanomedicine, Sensors},
pubstate = {published},
tppubtype = {article}
}
High-aspect-ratio photonic crystal air-hole fabrication on bulk Lithium Niobate (LN) substrates is extremely difficult due to its inherent resistance to etching, resulting in conical structures and high insertion losses. Here, we propose a novel coupled resonator photonic crystal (CRPC) design, combining a coupled resonator approach with that of Bragg gratings. CRPC design parameters were optimized by analytical calculations and FDTD simulations. CRPC structures with optimized parameters were fabricated and electrooptically tested on bulk LN annealed proton exchange waveguides. Low insertion loss and large electrooptic effect were observed with the fabricated devices, making the CRPC design a promising structure for electrooptic device applications.
370.
Baldwin, Paige; Shanmugam, Ilanchezhian; Tangutoori, Shifalika; Ohman, Anders; Dinulescu, Daniela; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{baldwin2015abstract,
title = {Abstract B35: Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy},
author = {Paige Baldwin and Ilanchezhian Shanmugam and Shifalika Tangutoori and Anders Ohman and Daniela Dinulescu and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy exploits a synthetic lethality strategy in ovarian cancers specifically endowed with inherent damage in DNA repair or transcription pathways. Here we report the first novel nanoformulations of PARP inhibitors NanoTalazoparib and NanoOlaparib, thus enabling a platform which provides a safe vehicle for parenteral administration specifically targeted to the tumor, thereby increasing the bioavailability while reducing systemic toxicity.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.
Methods: Three nanoparticle (∼120nm size) formulations NanoOlaparib, NanoOlaparibPt and NanoTalazoparib, were successfully formulated and tested in vitro and in vivo on several cancer cell lines. Ovarian Cancer cell lines tested include KURAMOCHI, SKOV3, and OVSAHO, JHOS2 PA1, COV318, 403/ 404 (derived from tumors of BRCA2-/-¬, PTEN-/-, / TP53mut mice) and 4306 / 4412 (developed from conditional LSL-K-rasG12D/+/PTENloxP/loxP) mice. IC50s were determined with an MTS assay. Radiosensitization studies with NanoOlaparib were carried out on prostate cancer cell lines LNCAP, PC3, and FK01 (derived from PTEN-/P53- mice tumors). In vivo studies were carried out with iv or ip administration.
Results: In vitro studies The murine cell lines, 403, 404 were highly sensitive to this treatment due to the triply mutated genomic profile. The high sensitivity of 4412 and 4306 cell lines suggests that PTEN deletion confers similar sensitivity to PARP inhibitors as a BRCA2 deletion. The PA1 is highly sensitive to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Strong radiosensitization was observed in the prostate cancer cell lines.
NanoTalazoparib is 10-100 times more potent than NanoOlaparib. The cell line dependence is similar to NanoOlaparib except for the overall lower magnitudes.
In vivo studies In a pilot study in an endometrial OvCa murine model with KRaS-PTEN deletion, bioluminescence images show tumor suppression of more than a nearly a factor of 3. Studies in BRCA2-/-¬/ PTEN-/-/TP53mut OvCa GEMM also showed good therapeutic response to i.p. administration. In vivo studies in prostate cancer models showed greater tumor accumulation and tumor reduction with NanoOlaparib.
Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully demonstrated for in vitro and in vivo administrations. All formulations were well tolerated.. These results show that NanoOlaparib and NanoTalazoparib amplify the therapeutic efficacy of PARP inhibition and imply a very promising role for the nanoformulation in ovarian and other cancers.
This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092.
Citation Format: Paige Baldwin, Ilanchezhian Shanmugam, Shifalika Tangutoori, Anders Ohman, Daniela Dinulescu, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Nanoformulations of PAPR inhibitors nanoolaparib and nanotalazoparib for targeted cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B35.
©2015 American Association for Cancer Research.
369.
Belz, Jodi; Liby, Karen; Baldwin, Paige; Kumar, Rajiv; van de Ven, Anne L; Cormack, Robert; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{belz2015abstract,
title = {Abstract B42: Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer},
author = {Jodi Belz and Karen Liby and Paige Baldwin and Rajiv Kumar and Anne L van de Ven and Robert Cormack and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.
Abstract
The breast cancer-associated gene 1 (Brca1) is the most frequently mutated tumor suppressor gene found in familial breast cancers. Mutations of the gene modulate many cellular functions including DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. Poly-ADP-Ribose Polymerase (PARP) inhibitor therapy can produce cell death in cancers with genetic predispositions for impaired DNA repair or transcription pathways such as Brca1 mutants. Here we report a novel biodegradable implant for the local delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib in contrast to low bioavailability and toxicity associated with oral delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib. The implants were characterized in vitro using SEM and HPLC, and the release kinetic studies were carried out in PBS buffer (pH 6.0) at 37°C. The IC50 was determined using an MTS assay in breast cancer cell lines derived from Brca1 Co/Co; MMTV-Cre; p53+/−mice. In vivo studies were carried out in Brca1 Co/Co; MMTV-Cre; p53+/− mice. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle.
Results: In vitro studies
The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses. Breast cancer cell lines W0069 and W780, derived from Brca1 Co/Co; MMTV-Cre; p53+/− mice were highly sensitive to Talazoparib, most likely due to Brca1 mutation. PARP expression was examined via western blot analysis.
In vivo studies
In vivo studies using sustained drug release implants loaded with Talazoparib were also carried out in Brca1Co/Co;MMTV-Cre;p53+/- genetically engineered mice with 1 or more spontaneous breast tumors. Following a one-time implantation, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. Talazoparib dosing appeared to be well tolerated by the mice. Histology samples were taken from sacrificed mice and immunohistochemistry are currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of Talazoparib was observed in vitro and in vivo. The Talazoparib-loaded implants represent a novel delivery route that was well-tolerated. Sustained release of Talazoparib appears to amplify the therapeutic efficacy of PARP inhibition and is a promising new route for the treatment of highly aggressive breast cancer models.
We would like to acknowledge the Breast Cancer Research Foundation. This work was supported by the Army- W81XWH-14-1-0092 and Northeastern University – Dana Farber Cancer Institute collaborative grant.
Citation Format: Jodi Belz, Karen Liby, Paige Baldwin, Rajiv Kumar, Anne L. van de Ven, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib from bioedgradable implant for treatment of BRCA1-mutated breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B42.
©2015 American Association for Cancer Research.
368.
Kumar, Rajiv; Belz, Jodi; Shanmugam, Ilanchezhian; Ngwa, Wilfred; Berbeco, Ross; Makrigiorgos, Mike; Sridhar, Srinivas
Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{kumar2015abstract,
title = {Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy},
author = {Rajiv Kumar and Jodi Belz and Ilanchezhian Shanmugam and Wilfred Ngwa and Ross Berbeco and Mike Makrigiorgos and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
publisher = {American Association for Cancer Research},
abstract = {Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.
Abstract
The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs.
Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women's Hospital.
Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.
©2015 American Association for Cancer Research.
367.
TANGUTOORI, Shifalika; Sridhar, Srinivas
Nanoparticle drug delivery system and method of treating cancer and neurotrauma Miscellaneous
2015.
Abstract | BibTeX | Tags: Nanomedicine
@misc{tangutoori2015nanoparticle,
title = {Nanoparticle drug delivery system and method of treating cancer and neurotrauma},
author = {Shifalika TANGUTOORI and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
abstract = {The invention provides pharmaceutical formulations of inhibitors for poly (ADP-ribose) polymerase (PARP) enzyme. The formulations can be used in the treatment and prevention of cancer as well as the treatment of neurotrauma and neurodegenerative diseases. The PARP inhibitor is delivered in the form of nanoparticles that provide efficient delivery of the inhibitor into cancer cells or other cells and release of the inhibitor within the cells. In treating cancer, the result is killing of tumor cells, whereas in treatment of neurotrauma and neurodegenerative disease, the result is preservation of cell function.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {misc}
}
The invention provides pharmaceutical formulations of inhibitors for poly (ADP-ribose) polymerase (PARP) enzyme. The formulations can be used in the treatment and prevention of cancer as well as the treatment of neurotrauma and neurodegenerative diseases. The PARP inhibitor is delivered in the form of nanoparticles that provide efficient delivery of the inhibitor into cancer cells or other cells and release of the inhibitor within the cells. In treating cancer, the result is killing of tumor cells, whereas in treatment of neurotrauma and neurodegenerative disease, the result is preservation of cell function.
366.
Clarke, Nicole; Biscocho, Jewison; Kwei, Kevin A; Davidson, Jean M; Sridhar, Sushmita; Gong, Xue; Pollack, Jonathan R
Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer Journal Article
In: PloS one, vol. 10, no. 11, 2015.
Abstract | BibTeX | Tags: Nanomedicine
@article{clarke2015integrative,
title = {Integrative genomics implicates EGFR as a downstream mediator in NKX2-1 amplified non-small cell lung cancer},
author = {Nicole Clarke and Jewison Biscocho and Kevin A Kwei and Jean M Davidson and Sushmita Sridhar and Xue Gong and Jonathan R Pollack},
year = {2015},
date = {2015-01-01},
journal = {PloS one},
volume = {10},
number = {11},
publisher = {Public Library of Science},
abstract = {NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis.},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
NKX2-1, encoding a homeobox transcription factor, is amplified in approximately 15% of non-small cell lung cancers (NSCLC), where it is thought to drive cancer cell proliferation and survival. However, its mechanism of action remains largely unknown. To identify relevant downstream transcriptional targets, here we carried out a combined NKX2-1 transcriptome (NKX2-1 knockdown followed by RNAseq) and cistrome (NKX2-1 binding sites by ChIPseq) analysis in four NKX2-1-amplified human NSCLC cell lines. While NKX2-1 regulated genes differed among the four cell lines assayed, cell proliferation emerged as a common theme. Moreover, in 3 of the 4 cell lines, epidermal growth factor receptor (EGFR) was among the top NKX2-1 upregulated targets, which we confirmed at the protein level by western blot. Interestingly, EGFR knockdown led to upregulation of NKX2-1, suggesting a negative feedback loop. Consistent with this finding, combined knockdown of NKX2-1 and EGFR in NCI-H1819 lung cancer cells reduced cell proliferation (as well as MAP-kinase and PI3-kinase signaling) more than knockdown of either alone. Likewise, NKX2-1 knockdown enhanced the growth-inhibitory effect of the EGFR-inhibitor erlotinib. Taken together, our findings implicate EGFR as a downstream effector of NKX2-1 in NKX2-1 amplified NSCLC, with possible clinical implications, and provide a rich dataset for investigating additional mediators of NKX2-1 driven oncogenesis.
365.
Debay, Ann Chiaramonti C; Ozturk, Birol; de Luna Bugallo, Andres; Panaitescu, Eugene; Liu, Fangze; Vargas, Anthony; Jiang, Xueping; Yavuzcetin, Ozgur; Alnaji, Majed; Zhao, Yongui; others,
Atomically thin layers of BNCO with tuneable composition Technical Report
2015.
Abstract | BibTeX | Tags: Nanomedicine
@techreport{debay2015atomically,
title = {Atomically thin layers of BNCO with tuneable composition},
author = {Ann Chiaramonti C Debay and Birol Ozturk and Andres de Luna Bugallo and Eugene Panaitescu and Fangze Liu and Anthony Vargas and Xueping Jiang and Ozgur Yavuzcetin and Majed Alnaji and Yongui Zhao and others},
year = {2015},
date = {2015-01-01},
abstract = {Atomically thin ternary compounds/alloys of boron, nitrogen and carbon have generated significant excitement as they provided the first instance of a tuneable 2D material that affords rich physics as well applications potentials. Interestingly, the crucial role and the possible inclusion of oxygen in the 2D-BNC lattice have never been investigated. Here, we present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon and oxygen, 2D-BNCO. Our experiments suggest and theoretical calculations corroborate stable configurations of a planar honeycomb 2D-BNCO lattice. We observed the growth of micron-scale 2D-BNCO domains within a graphene-rich matrix, and were able to control their area coverage and relative composition by varying the ratio of oxygen content in the growth setup. The introduction of oxygen into the BNC system induces a rich variety of electronic, optical, and magnetic properties.
CitationNano Letters},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {techreport}
}
Atomically thin ternary compounds/alloys of boron, nitrogen and carbon have generated significant excitement as they provided the first instance of a tuneable 2D material that affords rich physics as well applications potentials. Interestingly, the crucial role and the possible inclusion of oxygen in the 2D-BNC lattice have never been investigated. Here, we present the first report on an atomically thin quaternary alloy of boron, nitrogen, carbon and oxygen, 2D-BNCO. Our experiments suggest and theoretical calculations corroborate stable configurations of a planar honeycomb 2D-BNCO lattice. We observed the growth of micron-scale 2D-BNCO domains within a graphene-rich matrix, and were able to control their area coverage and relative composition by varying the ratio of oxygen content in the growth setup. The introduction of oxygen into the BNC system induces a rich variety of electronic, optical, and magnetic properties.
CitationNano Letters
CitationNano Letters
364.
Teh, James; Hanson, Robert; Sridhar, Srinivas
Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics Inproceedings
In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA 2015.
BibTeX | Tags: Nanomedicine
@inproceedings{teh2015targeting,
title = {Targeting integrin alpha v beta 3 receptors with multivalent RGD peptidomimetics},
author = {James Teh and Robert Hanson and Srinivas Sridhar},
year = {2015},
date = {2015-01-01},
booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY},
volume = {249},
organization = {AMER CHEMICAL SOC 1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
keywords = {Nanomedicine},
pubstate = {published},
tppubtype = {inproceedings}
}
363.
Wang, Haotian; Kumar, Rajiv; Nagesha, Dattatri; Jr, Richard I Duclos; Sridhar, Srinivas; Gatley, Samuel J
Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse Journal Article
In: Nuclear medicine and biology, vol. 42, no. 1, pp. 65–70, 2015.
Abstract | BibTeX | Tags: MRI, Nanomedicine
@article{wang2015integrity,
title = {Integrity of 111In-radiolabeled superparamagnetic iron oxide nanoparticles in the mouse},
author = {Haotian Wang and Rajiv Kumar and Dattatri Nagesha and Richard I Duclos Jr and Srinivas Sridhar and Samuel J Gatley},
year = {2015},
date = {2015-01-01},
journal = {Nuclear medicine and biology},
volume = {42},
number = {1},
pages = {65--70},
publisher = {Elsevier},
abstract = {Introduction
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.},
keywords = {MRI, Nanomedicine},
pubstate = {published},
tppubtype = {article}
}
Introduction
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.
Iron-oxide nanoparticles can act as contrast agents in magnetic resonance imaging (MRI), while radiolabeling the same platform with nuclear medicine isotopes allows imaging with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), modalities that offer better quantification. For successful translation of these multifunctional imaging platforms to clinical use, it is imperative to evaluate the degree to which the association between radioactive label and iron oxide core remains intact in vivo.
Methods
We prepared iron oxide nanoparticles stabilized by oleic acid and phospholipids which were further radiolabeled with 59Fe, 14C-oleic acid, and 111In.
Results
Mouse biodistributions showed 111In preferentially localized in reticuloendothelial organs, liver, spleen and bone. However, there were greater levels of 59Fe than 111In in liver and spleen, but lower levels of 14C.
Conclusions
While there is some degree of dissociation between the 111In labeled component of the nanoparticle and the iron oxide core, there is extensive dissociation of the oleic acid component.
