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/壳纳米复合颗粒（mNPs）来治疗肿瘤。通过将高亲和抗体片段或单链可变结构域（scFvs）偶联到mNPs上，可以靶向几种相关的癌症抗原。这项工作主要针对乳腺癌和卵巢癌，但适用于大多数癌症。这项工作是及时的，因为它已经在几个实验室（包括达特茅斯的Hoopes实验室）的小鼠模型中显示，通过在肿瘤中聚集磁性超顺磁性氧化铁纳米颗粒（SPIOs）并施加交变磁场（AMF），肿瘤细胞被破坏到这样的程度，要么恶性生长被显著延缓，要么肿瘤被完全摧毁。DCCNE将通过使用达特茅斯贝克实验室开发的mNPs来改进这些早期发现，与spio相比，mNPs在AMF中表现出更优越的加热行为。mNPs将被葡聚糖或磷脂包裹，并通过共价连接scFVs实现功能化，以实现肿瘤特异性靶向。将生产一系列新的靶向scFVs，并在小鼠和猪模型中检测mNP大小（15-100 nm）范围内的肿瘤积累。乳腺癌研究将涉及肿瘤治疗策略的开发，以确定将mNPs直接注射到肿瘤中与将抗体结合的mNPs通过注射到血管中并使用AMF破坏癌细胞来引入肿瘤的效果。卵巢癌研究将包括制定策略，以确定将抗体结合的mNPs引入临床前卵巢癌模型和游离临床标本的腹腔的治疗效果。此外，AMF将用于破坏癌细胞，同时还可以通过各种化学疗法引发抗肿瘤免疫。DCCNE将开发新的成像技术来确定mNPs的结合、位置和浓度，该技术基于光学比率荧光光谱和粒子布朗运动的磁波谱相结合，以产生两种新的协同方法来量化摄取和体内结合水平。动物工作将在毒理学、病理学和生物分布中心进行。生物统计学、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学合理条件。DCCNE将全面参与NCI CCNE跨联盟活动。

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.