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: 8551636
• 负责人: BALABHASKAR PRABHAKARPANDIAN
• 金额: $ 61.93万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551636
• 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; 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; screening; tumor; tumor microenvironment; 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.

描述（由申请人提供）：我们建议开发和演示一种新型微流体装置和试验，用于选择和优化输送载体，特别是用于向肿瘤输送药物的非病毒载体。肿瘤药物传递是一个复杂的现象，除药物或传递载体的理化性质外，还受多种因素的影响。其中一个关键因素是肿瘤微血管，它具有复杂的作用，包括对流输送、高间质压力和由于“漏血管”的存在而增强的血管通透性。目前肿瘤药物传递的体外模型过于简化，因此与体内表现的相关性较差。我们建议开发一种新的微流控平台，更准确地模拟肿瘤微环境，具有生理和形态上真实的微血管，包括内皮细胞内衬的渗漏毛细血管以及3D实体肿瘤。该装置将允许在活体条件下对运载工具的性能进行实时、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，其中嵌入了带有泄漏间隙的微血管网络。内皮细胞和宫颈肿瘤细胞三维球体在网络中共培养。利用基因传递纳米聚合物成功地进行了药物载体筛选。计划的II期增强包括对渗漏血管的优化，以及对乳腺、卵巢和肺肿瘤细胞培养设备的扩展。微流控装置筛选药物传递载体的能力，筛选靶向药物传递以及颗粒形状在基因传递之外的传递作用将被研究。一个多学科（工程和生物学）、具有丰富专业知识的行业-学术团队已经组建起来，以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，以及在药物发现中可用于研究现实肿瘤微环境中的药物功效。该产品将商业化给制药/生物技术公司、药物研究实验室和从事癌症研究和药物输送的大学/非营利中心。