SBIR-STTR Award

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. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) has made recommendations to address this unmet need, with an emphasis on drug-radiotherapy combinations. Recent studies suggest that intraperitoneal delivery of therapeutics, including radiotherapeutics (brachytherapy) can improve patient outcomes. Thus, this proposal is focused on the intraperitoneal delivery of mesoporous silica nanoparticles (MSNs) containing the  particle-emitting therapeutic radionuclide 166Ho (produced by neutron activation of stable holmium) in combination with the chemotherapeutic agent cisplatin for the treatment of ovarian cancer. The goal of this project is to advance the 166Ho-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 cisplatin. The first specific aim is to optimize the dosing regimen of 166Ho-MSN-based brachytherapy when administered in combination with cisplatin chemotherapy. Intraperitoneal administration doses and schedules of 166Ho-MSNs and cisplatin combination will be optimized and compared with either cisplatin, 166Ho-MSNs, non-radioactive 165Ho-MSNs, non-nanoparticle based 166Ho or saline. Two ovarian cancer cell lines with different progression profiles will be employed. Tumor growth will be determined by bioluminescence imaging of the luciferase over-expressed ovarian cancer cells, and absorbed radiation doses to the tumors and to surrounding tissues will be calculated based upon the tissue biodistribution and degree of tumor penetration of the 166Ho-MSNs. Survival will be expressed by Kaplan-Meier analysis to evaluate the efficacy improvement of the 166Ho-MSNs-cisplatin combination treatment. The second specific aim is to assess the toxicity and safety of the non-radioactive Ho-MSNs as well as the combination chemo-brachytherapy. All tissues collected from the studies conducted under aim 1 will be evaluated histologically for toxicity assessment. In addition, two standard ISO tests will be performed as an initial assessment of the safety of the non-radioactive Ho-MSNs. These include the intracutaneous injection test in the rabbit to assess the potential of the Ho-MSNs to produce irritation, and the systemic injection test in mice to evaluate systemic responses to the Ho-MSNs following intraperitoneal injection. The demonstration of efficacy and low tissue toxicity will strongly support the planned Phase II studies (cGMP manufacture/neutron activation, GLP toxicology, immunology, biocompatibility, microbiology, etc.). There is an urgent need to improve treatments and survival in metastatic ovarian cancer. The successful outcome of this translational project is expected to address these needs through a new paradigm for treating ovarian cancer patients.

Public Health Relevance Statement:
PROJECT NARRATIVE Treatment of cancer with both drugs and particles that emit radioactivity (brachytherapy) has emerged as an important treatment approach for many tumors. We have developed a nanoparticle that contains a radiation- emitting isotope called holmium-166 and have demonstrated its effectiveness in animal models of ovarian cancer. The goals of this project are to advance this product toward clinical trials by demonstrating its safety using standard toxicity tests, and to assess its efficacy in models of metastatic ovarian cancer when co-administered with the chemotherapy drug cisplatin.

Project Terms:
Animals; Brachytherapy; Radioisotope Brachytherapy; Radiation Brachytherapy; Curietherapy; Cause of Death; Cell Body; Cells; cis-Platinum; cis-Dichlorodiammineplatinum(II); cis-Diamminedichloroplatinum(II); cis-Diamminedichloroplatinum; cis-Diaminedichloroplatinum; cis platinum compound; cis dichlorodiammineplatinum; Platinum Diamminodichloride; Peyrone's Salt; Peyrone's Chloride; Dichlorodiammineplatinum; Cysplatyna; Cisplatinum; Cisplatina; Cis-platinum II Diamine Dichloride; Cis-platinum II; Cis-platinous Diamine Dichloride; Cis-dichloroammine Platinum (II); Cis-diamminedichloro Platinum (II); Cis-diamminedichloridoplatinum; Cis-diammine-dichloroplatinum; CDDP; Cisplatin; Clinical Trials; Connecticut; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Female; Goals; Holmium; Hospitals; IP injection; Intraperitoneal Injections; Isotopes; Luciferase Immunologic; Luciferases; Methods; Athymic Nude Mouse; Athymic Mice; Nude Mice; Microbiology; Morbidity; Morbidity - disease rate; mortality; Murine; Mice Mammals; Mice; Mus; tumor cell metastasis; cancer metastasis; Secondary Tumor; Secondary Neoplasm; Metastatic Tumor; Metastatic Neoplasm; Metastatic Mass; Metastatic Lesion; Metastasize; Metastasis; Neoplasm Metastasis; Neutrons; Brochures; Booklets; Pamphlets; Particle Size; Patients; Peritoneal Cavity; Greater sac of peritoneum; Phosphates; inorganic phosphate; Rabbits Mammals; Rabbits; Domestic Rabbit; Oryctolagus cuniculus; radiosensitizer; Radiosensitizing Drugs; Radiosensitizing Agents; Radiation-Sensitizing Drugs; Radiation Sensitizers; Radiation-Sensitizing Agents; Radioactivity; Radionuclides; Radioactive Isotopes; Radioisotopes; treatment with radiation; radio-therapy; radiation treatment; Radiotherapy; Radiotherapeutics; Radiation therapy; Recommendation; Research Institute; Researchers; Investigators; Research Personnel; Safety; Saline Solution; Saline; Ovarian Metastasis; Metastatic Malignant Tumor to the Ovary; Metastasis to Ovary; Metastatic Malignant Neoplasm to the Ovary; Tridymite; Silica; Sand; Cristobalite; Silicon Dioxide; Survival Rate; Suspension substance; Suspensions; Testing; Time; Body Tissues; Tissues; Toxicology; Treatment Schedule; Treatment Regimen; Treatment Protocols; United States; Universities; Woman; Treatment outcome; Mean Survival Times; Schedule; Immunology; base; quality assurance; improved; Clinical; Penetration; Phase; Histologic; Histologically; Chemicals; Progression-Free Survivals; Toxicity Tests; Toxicity Testing; Collaborations; Therapeutic; stable isotope; Exposure to; Shapes; cancer cell; Malignant Cell; Intravenous; irritation; Peritoneal; intraperitoneal; Protocols documentation; Protocol; Xenograft procedure; xeno-transplantation; xeno-transplant; Xenotransplantation; Xenograft; Heterologous Transplantation; Heterograft; radiation absorbed dose; biomaterial compatibility; biocompatibility; particle; success; tumor growth; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; Histopathology; Therapeutic Index; Malignant Female Reproductive System Neoplasm; gynecological malignancy; gynecologic malignancy; Malignant Tumor of the Female Reproductive System; Malignant Gynecologic Tumor; Malignant Gynecologic Neoplasm; Gynecological Cancer; Gynecologic Cancer; Female Reproductive Cancer; chemotherapeutic agent; Radiation; Modeling; response; cancer therapy; anticancer therapy; anti-cancer therapy; Malignant Neoplasm Treatment; Malignant Neoplasm Therapy; Cancer Treatment; Malignant neoplasm of ovary; ovarian cancer; Ovary Cancer; Malignant Tumor of the Ovary; Malignant Ovarian Tumor; Malignant Ovarian Neoplasm; Effectiveness; irradiation; palliative; Address; Dose; Tumor Burden; Tumor Load; Data; Gynecologic Oncologist; Radiation Oncologist; Radioactive; Cancer Patient; research clinical testing; clinical test; Clinical Testing; Clinical Evaluation; Patient-Focused Outcomes; Patient-Centered Outcomes; Patient outcome; Monitor; Process; Radiotherapy Research; Shipping; cellular imaging; cell imaging; Image; imaging; pre-clinical; preclinical; preclinical study; pre-clinical study; working group; work group; anticancer research; cancer research; anti-cancer research; nanotherapeutic; nano therapeutic; nanoparticle; nanosized particle; nano-sized particle; nano particle; Biodistribution; Outcome; Cancer cell line; Implant; chemotherapy; mouse model; murine model; tumor; overexpression; overexpress; treatment strategy; effective therapy; effective treatment; product development; preclinical efficacy; pre-clinical efficacy; phase 2 study; phase II study; Regimen; bioluminescence imaging; SKOV3 cells; SkOV-3; SKOV3; Injections; human model; safety assessment

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.

Public Health Relevance Statement:
PROJECT NARRATIVE Ovarian cancer is the fifth most common cause of cancer-related death among women. Current treatment options are often ineffective as highlighted by the high recurrence and chemoresistance rates. Nami Therapeutics is developing an improved treatment option for late-stage ovarian cancer that involves targeted delivery of nanoparticles that contain a radiation-emitting isotope called holmium-166. The treatment is tumor- specific, which reduces side effects, and can be used with current chemotherapeutic agents. Successful development of the technology has the potential to greatly enhance patient outcomes.

Project Terms:
Ascites; abdominal dropsy; hydroperitonia; hydrops abdominis; peritoneal dropsy; peritoneal exudate; Blood Circulation; Bloodstream; Circulation; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cause of Death; Cessation of life; Death; Diagnosis; Disease; Disorder; Extravasation; Leakage; Spillage; Goals; Holmium; Human; Modern Man; Isotopes; Methods; Nude Mice; Athymic Mice; Athymic Nude Mouse; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Neoplasm Metastasis; Particle Size; Patients; Peritoneal Cavity; Greater sac of peritoneum; Pharmacokinetics; Drug Kinetics; Radioactive Isotopes; Radionuclides; Radioisotopes; Radiation Dosimetry; radioassay; Radiometry; Radiotherapeutics; Radiotherapy; radiation treatment; treatment with radiation; Radiation therapy; Recurrent; Recurrence; Safety; Cristobalite; Sand; Silica; Tridymite; Silicon Dioxide; Time; Tissues; Body Tissues; Toxicology; United States; Woman; base; Organ; improved; Radionuclide therapy; therapeutic radionuclide; Ovarian; Clinical; Phase; Evaluation; Therapeutic; Deposit; Deposition; Intravenous; programs; chemo-/radio-therapy; chemo-radio-therapy; chemo-radiotherapy; chemoradiotherapy; radio-chemo-therapy; radio-chemotherapy; radiochemotherapy; chemoradiation; Peritoneal; intraperitoneal; 3-D; 3D; three dimensional; 3-Dimensional; Tumor Tissue; Radiation Dose; Radiation Dose Unit; physical property; stoichiometry; success; tech development; technology development; dosimetry; radiochemical; Toxicities; Toxic effect; Female Reproductive Cancer; Gynecologic Cancer; Gynecological Cancer; Malignant Gynecologic Neoplasm; Malignant Gynecologic Tumor; Malignant Tumor of the Female Reproductive System; gynecologic malignancy; gynecological malignancy; Malignant Female Reproductive System Neoplasm; chemotherapeutic agent; Radiation; Modeling; Adverse Experience; Adverse event; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; nano medicinal; nano medicine; nanomedicinal; nanomedicine; Address; Dose; Tumor Load; Tumor Burden; Data; Implant Radiation; internal radiation; Radioactive; in vivo; in vivo Model; Cancer Etiology; Cancer Cause; Cancer Model; CancerModel; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Small Business Technology Transfer Research; STTR; Xenograft Model; xenograft transplant model; xenotransplant model; Development; developmental; pre-clinical; preclinical; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; nanocarrier; nano carrier; nanoparticle; nano particle; nano-sized particle; nanosized particle; Biodistribution; targeted delivery; site targeted delivery; chemotherapy; mouse model; murine model; tumor; treatment strategy; effective therapy; effective treatment; systemic toxicity; Radiation exposure; efficacy study; clinical development; nanoparticle delivery; nano particle delivery; nanoparticle delivered; side effect; Chemoresistance; chemoresistant; chemotherapy resistance; chemotherapy resistant; Prognosis