Magnetic nanoparticle Immunotherapy against Ovarian Cancer

SUMIMARY项目(见说明)； 这项拟议的工作将确定利用磁性纳米颗粒(Mnp)治疗卵巢癌的潜力。 介导性热疗(MNPHT)。它将研究如何最好地同时摧毁肿瘤细胞和白细胞 抑制抗肿瘤免疫，支持血管生成。研究将在小鼠体内进行，使用同基因 小鼠卵巢癌和人卵巢癌异种移植及体外利用活体分离的人原代卵巢 包括肿瘤细胞、白细胞和内皮细胞在内的癌症制剂。我们在以下方面的丰富经验 卵巢癌研究将为mNP选择性靶向肿瘤和肿瘤支持细胞的设计提供信息。 假说是通过结合mNP介导物可以获得更好的治疗效果。 肿瘤细胞(包括化疗耐药癌细胞)的热消融 免疫抑制/促血管生成肿瘤白细胞和这些治疗将与标准 化疗。目的1确定使用mNPHT消除肿瘤相关疾病对肿瘤的影响 免疫活性小鼠卵巢癌模型中的吞噬细胞。Aim 2将使用相同的小鼠 肿瘤模型作为目标1，确定mNPHT在有或没有的情况下清除肿瘤细胞的有效性 肿瘤相关的白细胞耗尽或次佳化疗。目标3将确定以下因素的相互作用 不同靶向的mNP制剂与新鲜分离的人类肿瘤，使用独特的资源 从我们的大量新鲜分离的人卵巢中提取的多份等份冷冻细胞悬液 癌症。目标4将确定mNP-热疗作为针对人类的个体化治疗的有效性 免疫缺陷小鼠的卵巢癌移植瘤，并将确定如何最好地将这种治疗应用于 以便与其他无效剂量的顺铂协同作用。 在整个提案中，试剂、模型和实验的设计都是为了完成基于mNP的热疗作为一种治疗卵巢癌的新干预措施的临床前优化。这些研究将为mNPHT的后续临床测试与其他致命卵巢癌的治疗方法相结合铺平道路。 该项目将与所有其他项目和核心相互作用：它将利用纳米颗粒核心来制造mNPs，项目1将提供单链抗体结合的颗粒。项目2将在我们的卵巢肿瘤模型中测试他们的系统，项目3提供治疗设备，毒理学、病理学和生物分布核心将评估mNP的位置，生物统计、数据分析和计算核心将提供数据分析。

PROJECT SUMIMARY (See instructions); This proposed work will define the potential of treating ovarian cancer with magnetic nanoparticle (mNP) mediated hyperthermia (mNPHT). It will investigate how best to destroy both tumor cells and leukocytes that suppress antitumor immunity and support angiogenesis. Studies will be done in vivo in mice using syngeneic mouse ovarian cancer and human xenografts and in vitro using viable dissociated primary human ovarian cancer preparations that include tumor cells, leukocytes and endothelial cells. Our extensive experience with ovarian cancer research will inform the design of mNP selectively targeting tumor and tumor supporting cells. The hypothesis is that superior therapeutic benefits can be achieved by combining mNP-mediated thermoablation of tumor cells (including chemoresistant cancer cells) with thermoablation of crucial immunosuppressive/pro-angiogenic tumor leukocytes and these treatments will synergize with standard chemotherapies. Aim 1 will determine the impact on tumors of using mNPHT to eliminate tumor-associated phagocytic leukocytes in immunocompetent murine ovarian cancer models. Aim 2 will use the same murine tumor models as aim 1 to define the effectiveness of eliminating tumor cells with mNPHT, with or without tumor-associated leukocyte depletion or suboptimal chemotherapy. Aim 3 will determine the interaction of differently targeted mNP preparations with freshly dissociated human tumors, using a unique resource of multiple aliquots of frozen cell suspensions from our large bank of freshly dissociated human ovarian cancers. Aim 4 will define the effectiveness of mNP-hyperthermia as an individual treatment against human ovarian cancer xenografts in immunodeficient mice, and will determine how best to apply this treatment in order to synergize with otherwise ineffective doses of cisplatin. Throughout this proposal, the reagents, models and experiments have been designed to accomplish the preclinical optimization of mNP-based hyperthermia as a novel intervention against ovarian cancers. These studies will pave the way for subsequent clinical testing of mNPHT in combination with established therapeutic approaches for the treatment of otherwise lethal ovarian cancers. This project will interact with all other projects and cores: it will draw on the Nanoparticle Core for mNPs, Project 1 will provide ScFv-conjugated particles. Project 2 will test their system in our ovarian tumor models, Project 3 provides the treatment equipment, the Toxicology, Pathology, and Biodistribution Core will assess mNP location and the Biostatistics, Data Analysis, and Computation Core will provide data analysis.