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

项目摘要 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。 妇科恶性肿瘤妇女的死亡原因。尽管治疗策略取得了进展， 腹膜转移仍然是卵巢癌发病率和死亡率的主要原因。最近的研究 已经表明通过腹膜内（IP）递送治疗剂治疗腹膜转移可以 改善患者结局;然而，目前没有有效的IP递送疗法来解决 腹膜转移，特别是对于化疗耐药和复发患者。Nami Therapeutics（Nami） 为晚期卵巢癌开发一种基于IP的治疗方案。Nami的方法包括 含钬-166（166 Ho）介孔二氧化硅纳米粒子（166 Ho-MSN）的放射性核素治疗。166Ho- MSN以肿瘤特异性化疗的形式提供了治疗晚期卵巢癌的独特方法。 用于内部放射治疗的含放射性同位素的纳米载体。使用IP管理，166个Ho-MSN将被 直接输送到腹膜腔，在那里它们特异性地靶向肿瘤组织，限制辐射暴露 通过血液循环在整个身体，并反过来限制全身副作用，这是常见的其他 纳米药物和化疗药物静脉内输送。Nami成功完成了第一阶段 STTR项目，其证明了（1）通过用以下治疗在卵巢癌小鼠模型中提高存活率： 166 Ho-MSN单独使用和与化疗联合使用;以及（2）非放射性药物的有利安全性特征 组织和全身毒性评估中的165 Ho-MSN。第一阶段数据包进一步支持 通过第二阶段计划开发该技术，其目标是生成数据包， 提交给FDA以支持临床开发。具体而言，目标1将涉及努力产生 符合法规的含钬纳米颗粒。Aim 2将专注于生成目标产品简介 通过执行体内疗效研究，目标3将涉及执行关键毒性，生物动力学， 和剂量测定研究。成功完成第二阶段计划后，将向监管机构提交 FDA允许执行166 Ho-MSN治疗卵巢癌的临床安全性和有效性评价， 癌症转移

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.