PROJECT SUMMARY Ovarian cancer is the second most common gynecologic cancer in the United States and the most common cause of death among women with gynecologic malignancies. Despite advances in treatment strategies, peritoneal metastasis remains the primary cause of morbidity and mortality in ovarian cancer. Recent studies have suggested that treatment of peritoneal metastasis through intraperitoneal (IP) delivery of therapeutics can improve patient outcomes; however, there are currently no effective IP-delivered therapies for addressing peritoneal metastasis, especially for chemoresistant and recurrent patients. Nami Therapeutics (Nami) is developing an IP-based delivery treatment option for late-stage ovarian cancer. Nami’s approach involves holmium-166 (166Ho)-containing mesoporous silica nanoparticle (166Ho-MSN)-based radionuclide therapy. 166Ho- MSNs present a unique approach for treating advanced ovarian cancer in the form of a tumor-specific radioisotope-containing nanocarrier for internal radiation therapy. Using IP administration, 166Ho-MSNs will be delivered directly to the peritoneal cavity where they specifically target tumor tissues, limiting radiation exposure throughout the body via blood circulation, and in turn limiting systemic side effects that are common to other nanomedicines and chemotherapeutic agents delivered intravenously. Nami successfully completed a Phase I STTR program that demonstrated (1) enhanced survival in a mouse model of ovarian cancer by treatment with 166Ho-MSNs alone and in combination with chemotherapy; and (2) a favorable safety profile of non-radioactive 165Ho-MSNs in tissues and in systemic toxicity assessments. The Phase I data package supports further development of the technology through a Phase II program that has a goal of generating a data package to submit to the FDA to support of clinical development. Specifically, Aim 1 will involve efforts to generate regulatory-compliant holmium-containing nanoparticles. Aim 2 will focus on generating a target product profile through the execution of in vivo efficacy studies, and Aim 3 will involve the execution of critical toxicity, biokinetic, and dosimetry studies. Successful completion of the Phase II program will result in a regulatory submission to the FDA to allow for the execution of clinical safety and efficacy evaluations of 166Ho-MSNs for treating ovarian cancer metastases.