A NOVEL MICROFLUIDIC DEVICE FOR SELECTION AND OPTIMIZATION OF DRUG DELIVERY VEHIC

用于选择和优化药物输送载体的新型微流体装置

• 批准号: 8394872
• 负责人: BALABHASKAR PRABHAKARPANDIAN
• 金额: $ 63.33万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-08 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394872
• 关键词: A549; Adhesions; Affect; Antineoplastic Agents; Basic Science; Binding; Biological Assay; Biology; Biotechnology; Blood Vessels; Blood capillaries; Brain; Breast; Cell Line; Cells; Cervix Neoplasms; Coculture Techniques; Communication; Complex; Computer Simulation; DNA; Devices; Diffusion; Drug Delivery Systems; Drug vehicle; Endothelial Cells; Engineering; Environment; Gene Delivery; Hela Cells; Image; In Vitro; Indium; Industry; Label; Liposomes; Lung; Lung Neoplasms; MDA MB 231; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mammary Neoplasms; Methods; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Morphology; Non-Viral Vector; Ovarian; Pattern; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plastics; Polymers; Protocols documentation; Rattus; Reagent; Research; Role; Screening procedure; Shapes; Solid Neoplasm; Staging; Structure; Testing; Therapeutic; Time; Tissues; Universities; Vascular Permeabilities; Work; anticancer research; base; cancer cell; capillary; chemical property; design; drug discovery; drug efficacy; in vitro Model; in vivo; interest; interstitial; malignant breast neoplasm; meetings; nanopolymer; neoplastic cell; next generation; novel; novel strategies; ovarian neoplasm; particle; phase 2 study; pressure; prototype; tumor; uptake

DESCRIPTION (provided by applicant): We propose to develop and demonstrate a novel microfluidic device and assay for selection and optimization of delivery vehicles, specifically non-viral vectors for drug delivery to tumors. Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle's physico-chemical properties. A key factor is tumor microvasculature with complex effects including convective transport, high interstitial pressure and enhanced vascular permeability due to the presence of "leaky vessels". Current in vitro models of tumor drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. We propose to develop a novel microfluidic platform that models the tumor microenvironment more accurately, with physiologically and morphologically realistic microvasculature including endothelial cell lined leaky capillary vessels along with 3D solid tumors. This device will allow real-time, quantitative assessment of the performance of delivery vehicles under in vivo like conditions. In Phase I, we designed and fabricated prototypes of plastic microfluidic chips with embedded microvascular networks with leaky gaps. Endothelial cells and 3D spheroids of cervical tumor cells were co-cultured in the networks. Drug vehicle screening was successfully demonstrated using gene delivery nanopolymers. Planned Phase II enhancements include optimization of leaky vasculature in addition to extension of the device for culture of breast, ovary and lung tumor cells. The ability of the microfluidic device for screening of drug delivery vehicle screening for targeted drug delivery and the role of particle shape for delivery in addition to gene delivery wil be investigated. A multi-disciplinary (engineering and biology), industry-academic team with substantial expertise has been assembled for successful execution of this challenging project. The developed device will have critical applications both in basic research, where it can be used to develop next generation delivery vehicles, and in drug discovery where it can be used to study drug efficacy in realistic tumor microenvironment. The product will be commercialized to pharmaceutical/biotech firms, drug research labs and universities/non-profit centers engaged in cancer research and drug delivery. PUBLIC HEALTH RELEVANCE: The developed device will have critical applications both in basic research, where it can be used to characterize and develop next generation delivery vehicles, and in drug discovery where it can be used to study the efficacy of the drug in these realistic tumor microvascular networks. The product will be commercialized to pharmaceutical/biotech firms, drug research labs and universities/non-profit centers engaged in cancer research and drug delivery.

描述（由申请人提供）：我们提出开发和证明一种新型微流体装置和测定法，用于选择和优化递送载体，特别是用于药物递送至肿瘤的非病毒载体。肿瘤给药是一个复杂的现象，除了药物或载体的物理化学性质外，还受到多种因素的影响。一个关键因素是具有复杂效应的肿瘤微血管系统，包括对流转运、高间质压和由于“渗漏血管”的存在而增强的血管渗透性。目前的肿瘤药物递送的体外模型过于简化，结果显示与体内性能的相关性较差。我们建议开发一种新的微流体平台，其更准确地模拟肿瘤微环境，具有生理学和形态学上真实的微血管系统，包括内皮细胞内衬的渗漏毛细血管沿着与3D实体肿瘤。该装置将允许在体内类似条件下对递送载体的性能进行实时定量评估。在第一阶段，我们设计并制造了塑料微流控芯片的原型，其中嵌入了具有泄漏间隙的微血管网络。将内皮细胞和宫颈肿瘤细胞的三维球体在网络中共培养。使用基因递送纳米聚合物成功地证明了药物载体筛选。计划的II期增强包括优化渗漏血管系统，以及将器械扩展用于乳腺、卵巢和肺肿瘤细胞培养。将研究微流控装置用于筛选药物递送载体的能力、筛选靶向药物递送的能力以及除了基因递送之外颗粒形状对于递送的作用。一个多学科（工程和生物学），具有丰富的专业知识的行业学术团队已经组装成功执行这个具有挑战性的项目。开发的设备将在基础研究中具有关键应用，可用于开发下一代运载工具，并可用于研究药物在现实肿瘤微环境中的疗效。该产品将被商业化的制药/生物技术公司，药物研究实验室和大学/非营利中心从事癌症研究和药物输送。 公共卫生相关性：所开发的设备将在基础研究中具有关键应用，在基础研究中，它可用于表征和开发下一代运载工具，在药物发现中，它可用于研究药物在这些现实肿瘤微血管网络中的功效。该产品将被商业化的制药/生物技术公司，药物研究实验室和大学/非营利中心从事癌症研究和药物输送。