Nanoscale Coordination Polymers Co-deliver Chemotherapeutics and siRNAs for Efficacious Treatment of Resistant Ovarian Cancer

项目总结： 卵巢癌(OCA)是美国女性癌症死亡的第五大原因。从本质上讲 耐药和复发的卵巢癌是一种晚期疾病，无法用现有的治疗方法治愈。 考虑到肿瘤的分子和遗传异质性，我们假设有效的OCA治疗 可以通过确定在个别OCA患者的肿瘤中发现的基因异常来发展 设计个性化治疗，以克服患者特定的多药耐药性(MDR)。我们建议 开发坚固的纳米配位聚合物(NCP)，用于一线和二线OCA的联合传递 化疗药物(顺铂或顺铂加吉西他滨)和针对多药耐药基因的siRNA鸡尾酒。独一无二的 将阐明内体逃逸机制，并有望普遍适用于合理的设计 用于在体内高效输送生物制品的纳米载体。该项目不仅将提供新的基本见解 纳米医学的研究，也为个性化治疗的临床翻译带来了巨大的希望 抗药性OCA。 目的1：构建NCP/siRNAs，并评价其对OCA耐药细胞株的体外作用。两个NCP/siRNAs 将开发以化疗药物为核心，以外壳为靶向MDR的siRNAs的制剂，并 特色化的。体外基因沉默和细胞毒性将在耐药的OCA细胞中进行评估。 目的：评价NCP/siRNAs在耐药OCA小鼠原位肿瘤模型中的抗癌作用。这个 NCP/siRNAs的一般毒性和抗癌效果将在小鼠模型中进行评估。 目的3：通过在NCP/siRNAs外壳中掺入Her2/neu抗体片段来主动靶向NCP/siRNAs。 小蛋白Her2/neu抗体片段将连接到脂质上，并结合到外壳中 NCP/siRNAs和由此产生的纳米颗粒将在Her2/neu高表达和Her2/neu低表达的情况下进行测试 表达耐药的OCA肿瘤模型以评估药代动力学、肿瘤沉积和疗效的变化。 目的4：评价NCP/siRNAs和NCP/siRNAs/H2A在患者来源异种移植(PDX)中的抗癌效果。 耐药OCA小鼠模型。将分析MDR相关基因在OCA肿瘤PDX中的表达 梅奥诊所收集的样本。将设计个性化的治疗方案，需要化疗药物(S) 以及针对MDR基因的siRNA的选择。已确认的铂耐药肿瘤细胞将用于评估 NCP/siRNAs在PDX OCA小鼠原位模型中的抗癌作用来自HER-2/neu受体的肿瘤 阳性和阴性患者将进一步通过NCP/siRNAs/H2A进行抗癌疗效评估。 通过这些目标，我们寻求建立一种新的治疗耐药OCA的范例。NCP/siRNAs 可为OCA患者提供个性化治疗，在耐药中实现极大的抗癌效果 亚奥理事会。作为治疗宫颈癌和其他癌症的标准，基于顺铂的NCP/siRNAs可以有广泛的 对治疗其他耐药癌症的影响。

Project Summary: Ovarian cancer (OCa) is the fifth leading cause of cancer death for women in the United States. Intrinsically resistant and recurring ovarian cancers are a terminal disease that cannot be cured with existing therapeutics. Considering the molecular and genetic heterogeneity of tumors, we hypothesize that efficacious OCa therapy can be developed by determining the genetic abnormalities found in tumors of individual OCa patients and designing personalized therapy that can overcome patient-specific multi-drug resistance (MDR). We propose to develop robust nanoscale coordination polymers (NCPs) for the co-delivery of front-line and second-line OCa chemotherapeutics (cisplatin or cisplatin plus gemcitabine) and siRNA cocktails targeting MDR genes. A unique endosomal escape mechanism will be elucidated and is expected to be generally applicable to the rational design of nanocarriers for efficient delivery of biologics in vivo. This project will not only provide new fundamental insights nanomedicine research, but also holds great promise for clinical translation for the personalized treatment of resistant OCa. Aim 1: Develop NCP/siRNAs and evaluate their in vitro effects on resistant OCa cell lines. Two NCP/siRNAs formulations with chemotherapeutics in the core and siRNAs targeting MDR in the shell will be developed and characterized. The in vitro gene silencing and cytotoxicity will be evaluated in resistant OCa cells. Aim 2: Evaluate the anticancer efficacy of NCP/siRNAs in orthotopic mouse tumor models of resistant OCa. The general toxicity and anticancer efficacy of NCP/siRNAs will be assessed in mouse models. Aim 3: Actively target NCP/siRNAs by incorporating Her2/neu antibody fragments into the NCP/siRNAs shell. Small protein Her2/neu antibody fragments will be conjugated to a lipid and incorporated into the outer shell of NCP/siRNAs and the resulting nanoparticles will be tested in Her2/neu high expressing and Her2/neu low expressing resistant OCa tumor models to evaluate changes in pharmacokinetics, tumor deposition, and efficacy. Aim 4: Evaluate the anticancer efficacy of NCP/siRNAs and NCP/siRNAs/H2A in patient-derived xenograft (PDX) mouse models of resistant OCa. The expression of MDR-associated genes will be analyzed in OCa tumor PDX samples collected by the Mayo clinic. Personalized therapy will be designed entailing chemotherapeutic agent(s) and the choice of siRNAs targeting MDR genes. Confirmed platinum-resistant tumor cells will be used to evaluate the anticancer efficacy of NCP/siRNAs in orthotopic PDX OCa mouse models. Tumors from Her-2/neu receptor positive and negative patients will be further evaluated for anticancer efficacy by NCP/siRNAs/H2A. Through these aims we seek to establish a new paradigm for the treatment of resistant OCa. NCP/siRNAs can provide personalized therapy for OCa patients and achieve greatly enhanced anticancer efficacy in resistant OCa. As the standards of care for cervical and other cancers, cisplatin-based NCP/siRNAs can have broad impact on treating other resistant cancers.