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

基于纳米粒子的腹腔内联合放化疗治疗卵巢癌转移

• 批准号: 10687104
• 负责人: Michael Jay
• 金额: $ 97.1万
• 依托单位: NAMI THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687104
• 关键词: 3-Dimensional; Address; Adverse event; Ascites; Biodistribution; Blood Circulation; Cancer Etiology; Cancer Model; Cause of Death; Cessation of life; Chemoresistance; Clinical; Data; Deposition; Development; Diagnosis; Disease; Dose; Drug Kinetics; Evaluation; Extravasation; Goals; Greater sac of peritoneum; Holmium; Human; Intravenous; Isotopes; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modeling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nude Mice; Organ; Ovarian; Particle Size; Patient-Focused Outcomes; Patients; Peritoneal; Phase; Prognosis; Radiation; Radiation Dose Unit; Radiation exposure; Radiation therapy; Radioactive; Radioisotopes; Radiometry; Radionuclide therapy; Recurrence; Recurrent disease; Safety; Silicon Dioxide; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Tumor Burden; Tumor Tissue; United States; Woman; Xenograft Model; cancer therapy; chemoradiation; chemotherapeutic agent; chemotherapy; clinical development; dosimetry; effective therapy; efficacy evaluation; efficacy study; improved; in vivo; in vivo Model; internal radiation; intraperitoneal; mortality; mouse model; nanocarrier; nanomedicine; nanoparticle; nanoparticle delivery; physical property; pre-clinical; programs; radiochemical; side effect; stoichiometry; success; systemic toxicity; targeted delivery; technology development; treatment strategy; tumor

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.

项目概要 卵巢癌是美国第二常见的妇科癌症，也是最常见的妇科癌症 尽管治疗策略取得了进步，但妇科恶性肿瘤女性的死亡原因。 腹膜转移仍然是卵巢癌发病和死亡的主要原因。 已经建议通过腹膜内（IP）递送治疗剂来治疗腹膜转移 改善患者的治疗效果；然而，目前尚无有效的 IP 治疗方法来解决 腹膜转移，特别是对于化疗耐药和复发的患者。 Nami 的方法涉及开发一种基于 IP 的治疗方案。 含钬166 (166Ho)的介孔二氧化硅纳米粒子(166Ho-MSN)为基础的放射性核素治疗。 MSN 提供了一种以肿瘤特异性药物形式治疗晚期卵巢癌的独特方法。 使用IP管理，将含有放射性同位素的纳米载体用于内部放射治疗。 直接输送到腹膜腔，专门针对肿瘤组织，限制辐射暴露 通过血液循环遍及全身，从而限制其他药物常见的全身副作用 纳米药物和化疗药物静脉注射成功完成了第一阶段。 STTR 计划证明 (1) 通过使用以下药物治疗可提高卵巢癌小鼠模型的存活率 166Ho-MSN 单独使用以及与化疗联合使用；(2) 良好的非放射性安全性； 165Ho-MSN 在组织和全身毒性评估中的作用 I 期数据包进一步支持。 通过第二阶段计划开发该技术，其目标是生成数据包 具体来说，目标 1 将涉及产生的努力，以支持临床开发。 目标 2 将重点关注生成目标产品概况。 通过执行体内功效研究，目标 3 将涉及执行关键毒性、生物动力学、 成功完成第二阶段计划将导致向监管机构提交申请。 FDA 允许对 166Ho-MSN 治疗卵巢进行临床安全性和有效性评估 癌症转移。