Nanoparticle-based Intraperitoneal Delivery of Combined Chemo-brachytherapy for Treatment of Ovarian Cancer Metastases

PROJECT SUMMARY ABSTRACT Ovarian cancer is the second most common gynecologic cancer in the United States and the most common cause of death among women with gynecologic malignanciesDespite advances in treatment strategiesperitoneal metastasis remains the primary cause of morbidity and mortality in ovarian cancerThe National Cancer Research Institute Clinical and Translational Radiotherapy Research Working GroupCTRadhas made recommendations to address this unmet needwith an emphasis on drug radiotherapy combinationsRecent studies suggest that intraperitoneal delivery of therapeuticsincluding radiotherapeuticsbrachytherapycan improve patient outcomesThusthis proposal is focused on the intraperitoneal delivery of mesoporous silica nanoparticlesMSNscontaining theparticle emitting therapeutic radionuclideHoproduced by neutron activation of stable holmiumin combination with the chemotherapeutic agent cisplatin for the treatment of ovarian cancerThe goal of this project is to advance theHo MSN product toward clinical trials by demonstrating its safety and efficacy in preclinical animal models in the treatment of peritoneal metastases of ovarian cancer when co administered with cisplatinThe first specific aim is to optimize the dosing regimen ofHo MSN based brachytherapy when administered in combination with cisplatin chemotherapyIntraperitoneal administration doses and schedules ofHo MSNs and cisplatin combination will be optimized and compared with either cisplatinHo MSNsnon radioactiveHo MSNsnon nanoparticle basedHo or salineTwo ovarian cancer cell lines with different progression profiles will be employedTumor growth will be determined by bioluminescence imaging of the luciferase over expressed ovarian cancer cellsand absorbed radiation doses to the tumors and to surrounding tissues will be calculated based upon the tissue biodistribution and degree of tumor penetration of theHo MSNsSurvival will be expressed by Kaplan Meier analysis to evaluate the efficacy improvement of theHo MSNs cisplatin combination treatmentThe second specific aim is to assess the toxicity and safety of the non radioactive Ho MSNs as well as the combination chemo brachytherapyAll tissues collected from the studies conducted under aimwill be evaluated histologically for toxicity assessmentIn additiontwo standard ISO tests will be performed as an initial assessment of the safety of the non radioactive Ho MSNsThese include the intracutaneous injection test in the rabbit to assess the potential of the Ho MSNs to produce irritationand the systemic injection test in mice to evaluate systemic responses to the Ho MSNs following intraperitoneal injectionThe demonstration of efficacy and low tissue toxicity will strongly support the planned Phase II studiescGMP manufacture neutron activationGLP toxicologyimmunologybiocompatibilitymicrobiologyetcThere is an urgent need to improve treatments and survival in metastatic ovarian cancerThe successful outcome of this translational project is expected to address these needs through a new paradigm for treating ovarian cancer patients PROJECT NARRATIVE Treatment of cancer with both drugs and particles that emit radioactivitybrachytherapyhas emerged as an important treatment approach for many tumorsWe have developed a nanoparticle that contains a radiationemitting isotope called holmiumand have demonstrated its effectiveness in animal models of ovarian cancerThe goals of this project are to advance this product toward clinical trials by demonstrating its safety using standard toxicity testsand to assess its efficacy in models of metastatic ovarian cancer when co administered with the chemotherapy drug cisplatin