Magnetic nanoparticle Immunotherapy against Ovarian Cancer

项目摘要（见说明）; 这项拟议的工作将确定磁纳米粒子（mNP）治疗卵巢癌的潜力 介导的高热（mNPHT）。它将研究如何最好地破坏肿瘤细胞和白细胞， 抑制抗肿瘤免疫和支持血管生成。研究将在小鼠体内进行，使用同基因 小鼠卵巢癌和人异种移植物以及体外使用活的分离的原代人卵巢癌 包括肿瘤细胞、白细胞和内皮细胞的癌症制剂。我们的丰富经验， 卵巢癌研究将为选择性靶向肿瘤和肿瘤支持细胞的mNP的设计提供信息。 该假说是，通过联合mNP介导的免疫抑制剂，可以获得上级治疗益处。 肿瘤细胞（包括化学抗性癌细胞）的热消融， 免疫抑制/促血管生成肿瘤白细胞，并且这些治疗将与标准的 化疗目的1将确定使用mNPHT消除肿瘤相关的肿瘤抑制剂对肿瘤的影响。 免疫活性小鼠卵巢癌模型中的吞噬白细胞。目标2将使用相同的小鼠 肿瘤模型作为目标1，以确定用mNPHT消除肿瘤细胞的有效性， 肿瘤相关白细胞耗竭或次优化疗。目标3将确定以下方面的相互作用： 不同的靶向mNP制剂与新鲜解离的人肿瘤，使用独特的资源， 来自我们的大型新鲜分离的人卵巢癌细胞库的冷冻细胞悬液的多个等分试样 癌的目的4将确定mNP-热疗作为针对人类的个体化治疗的有效性 卵巢癌异种移植免疫缺陷小鼠，并将确定如何最好地应用这种治疗， 以便与其他无效剂量的顺铂协同作用。 在整个提案中，试剂，模型和实验已被设计为完成基于mNP的热疗作为一种新的干预卵巢癌的临床前优化。这些研究将为随后的mNPHT临床试验铺平道路，并与已建立的治疗方法相结合，用于治疗其他致命的卵巢癌。 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用于mNP，项目1将提供ScFv缀合的颗粒。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位置，生物统计学，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.