Dartmouth Center for Cancer Nanotechnology Excellence

达特茅斯癌症纳米技术卓越中心(DCCNE)专注于开发和使用新型抗体靶向磁性铁/氧化铁核/壳纳米复合粒子(MNPs)用于治疗肿瘤。一些相关的癌症抗原将通过将高亲和力抗体片段或单链可变区(ScFv)连接到mNPs来靶向。这项努力的重点是乳腺癌和卵巢肿瘤，但适用于大多数癌症。这项工作是及时的，因为它已经表明，通过使用包括达特茅斯大学霍普斯实验室在内的几个实验室的小鼠模型，通过在肿瘤中积聚磁性超顺磁性氧化铁纳米颗粒(SPIO)并施加交变磁场(AMF)，肿瘤细胞受到的损害程度要么显著减缓，要么肿瘤完全摧毁。DCCNE将通过使用在达特茅斯的贝克实验室开发的mNPs来改进这些早期的发现，与SPIO相比，mNPs在AMF中显示出更好的加热行为。MNPs将被葡聚糖或磷脂包裹，并通过共价连接scFv来功能化，以实现肿瘤特异性靶向。将产生一系列新的靶向单链抗体，并将在小鼠和猪模型中检查一系列mNP大小(15-100 nm)的肿瘤聚集。乳腺癌的工作将包括开发一种肿瘤治疗策略，以确定将mNPs直接注射到肿瘤中的效果，还是通过向血管系统注射抗体连接的mNPs到肿瘤中，并使用AMF来破坏癌细胞。卵巢癌的工作将包括制定策略，以确定将抗体结合的mNPs引入临床前卵巢癌模型和分离的临床标本的腹膜腔的治疗效果。此外，AMF将用于破坏癌细胞，同时还将通过各种化疗诱导抗肿瘤免疫。DCCNE将开发新的成像技术来确定mNPs的结合、位置和浓度，其基础是结合光学比率荧光光谱和颗粒布朗运动的磁光谱，以产生两种新的、协同的方法来量化体内摄取和结合水平。动物工作将在毒理学、病理学和生物分配核心进行。生物统计、数据分析和计算核心将分析测量结果并计算磁场，以获得动物实验的最佳生物合理条件。DCCNE将全面参与NCI CCNE跨联盟活动。 公共卫生相关性：达特茅斯CCNE将使用针对肿瘤的新型生物兼容磁性纳米颗粒，在施加交变磁场时摧毁或严重损害肿瘤。这项工作还将检验这种方法与化疗相结合产生抗肿瘤免疫的协同作用。DCCNE将专注于乳腺癌和卵巢癌的治疗，但开发的方法可能适用于任何类型的癌症。

The Dartmouth Center of Cancer Nanotechnology Excellence (DCCNE) focuses on the development and use of novel antibody-targeted magnetic iron/iron oxide core/shell nanocomposite particles (mNPs) for the treatment of tumors. Several relevant cancer antigens will be targeted by conjugating high-affinity antibody fragments or single-chain variable domains (scFvs) to mNPs. The effort focuses on breast cancer and ovarian tumors, but is applicable to most cancers. The work is timely because it has been shown, using mouse models in several laboratories, including the Hoopes laboratory at Dartmouth, that by amassing magnetic superparamagnetic iron oxide nanoparticles (SPIOs) in a tumor and applying an alternating magnetic field (AMF), tumor cells are damaged to such an extent that either malignant growth is significantly retarded or the tumor is completely destroyed. The DCCNE will improve upon these earlier findings by using mNPs, developed in the Baker lab at Dartmouth, that show superior heating behavior in an AMF when compared with SPIOs. The mNPs will be coated with either dextran or phospholipids and functionalized by covalently attaching scFVs to achieve tumor-specific targeting. A range of novel targeting scFVs will be produced, and tumor accumulation will be examined for a range of mNP sizes (15-100 nm) in mouse and pig models. The breast cancer work will involve development of a tumor treatment strategy to determine the efficacy of direct injection of mNPs into a tumor versus introduction of antibody-conjugated mNPs to the tumor through injection into the vasculature and using an AMF to damage the cancer cells. The ovarian cancer work will involve development of strategies to determine the therapeutic effectiveness of introducing antibody-conjugated mNPs into the peritoneal cavity of preclinical ovarian cancer models and dissociated clinical specimens. In addition, an AMF will be used to damage cancer cells while also eliciting anti-tumor immunity using various chemotherapies. The DCCNE will develop new imaging technologies to determine the binding, location, and concentration of the mNPs based on combining optical ratiometric fluorescence spectroscopy with magnetic spectroscopy of particle Brownian motion in order to produce two novel and synergistic approaches to quantify uptake and the level of binding in vivo. The animal work will occur in the Toxicology, Pathology, and Biodistribution Core. The Biostatistics, Data Analysis, and Computation Core will analyze measurements and calculate the magnetic field for the optimum biologically justified conditions for the animal experiments. The DCCNE will participate fully in NCI CCNE Trans-Alliance activities. Public Health Relevance: The Dartmouth CCNE will use novel biocompatible magnetic nanoparticles targeted to tumors to destroy or severely damage the tumors when an alternating magnetic field is applied. The work will also examine the synergy of combining this approach with chemotherapy to produce anti-tumor immunity. The DCCNE will be focus on breast cancer and ovarian cancer treatment, but the approaches developed potentially can be used for any type of cancer.