Dartmouth Center for Cancer Nanotechnology Excellence

达特茅斯癌症纳米技术卓越中心

• 批准号: 8144365
• 负责人: Ian Baker
• 金额: $ 241.54万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144365
• 关键词: Dartmouth; Center; Cancer; Nanotechnology; Excellence

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.

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）治疗肿瘤。将通过将高亲和力抗体片段或单链可变结构域（scFv）缀合至mNP来靶向几种相关的癌抗原。这项工作主要集中在乳腺癌和卵巢肿瘤，但适用于大多数癌症。这项工作是及时的，因为它已经被证明，使用小鼠模型在几个实验室，包括达特茅斯的Hoopes实验室，通过在肿瘤中积累磁性超顺磁性氧化铁纳米颗粒（SPIO）并施加交变磁场（AMF），肿瘤细胞被破坏到这样的程度，即恶性生长被显着延缓或肿瘤被完全摧毁。DCCNE将通过使用达特茅斯贝克实验室开发的mNP来改进这些早期的发现，与SPIO相比，mNP在AMF中显示出上级加热行为。mNP将用葡聚糖或磷脂包被，并通过共价连接scFv来官能化以实现肿瘤特异性靶向。将产生一系列新的靶向scFV，并将在小鼠和猪模型中检查一系列mNP尺寸（15-100 nm）的肿瘤蓄积。乳腺癌工作将涉及开发肿瘤治疗策略，以确定将mNP直接注射到肿瘤中与通过注射到脉管系统中并使用AMF破坏癌细胞将抗体缀合的mNP引入肿瘤的功效。卵巢癌工作将涉及开发策略，以确定将抗体缀合的mNP引入临床前卵巢癌模型和分离的临床标本的腹膜腔中的治疗效果。此外，AMF将用于破坏癌细胞，同时还使用各种化疗引发抗肿瘤免疫。DCCNE将开发新的成像技术，以确定结合，位置和浓度的mNPs的基础上结合光学比率荧光光谱与磁光谱的颗粒布朗运动，以产生两种新的和协同的方法来量化摄取和结合的水平在体内。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动物实验最佳生物学合理条件的磁场。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将使用新的生物相容性磁性纳米粒子靶向肿瘤，当施加交变磁场时，摧毁或严重损害肿瘤。这项工作还将研究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，但开发的方法可能用于任何类型的癌症。