A Novel Microfluidic Device for Selection and Optimization of Drug Delivery Vehic

描述（由申请人提供）：我们提出开发和证明一种新的微流体装置和测定，用于选择和优化药物递送载体，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。一个主要因素是肿瘤微血管系统，具有复杂的影响，包括对流血液运输、高间质压和由于“渗漏血管”而增强的血管渗透性。目前肿瘤药物递送的体外模型过于简化，因此高估了体内性能，可预测性非常差。我们建议开发一种新的微流体装置，其精确地模拟肿瘤微环境，具有生理学和形态学上精确的微血管系统，包括泄漏的内皮层沿着与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，我们将设计和制造嵌入微血管网络的塑料微流控芯片原型。内皮细胞和肿瘤细胞将在这些网络中培养。将使用两种充分表征的聚合物（一种用于卵巢癌治疗的临床研究）评估该器械在定量递送方面的潜力。计划的II期增强包括肿瘤特异性微血管系统和在基质细胞存在下用内皮细胞培养肿瘤细胞的优化方法。产品开发将进行批量生产和接口与标准成像设备。将开发用于数据记录、分析和储存的定制软件。该产品已经得到了一些潜在客户/最终用户的热情推荐。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了这个具有挑战性的项目的执行。开发的设备将在基础研究中具有关键应用，它可用于表征和开发下一代递送载体，以及在药物发现中，它可用于研究药物在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。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。

DESCRIPTION (provided by applicant): We propose to develop and demonstrate a novel microfluidic device and assay for selection and optimization of drug 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 primary factor is tumor microvasculature with complex effects including convective blood transport, high interstitial pressure and enhanced vascular permeability due to "leaky vessels". Current in-vitro models of tumor drug delivery are oversimplified and, as a result, overestimate in-vivo performance with very poor predictability. We propose to develop a novel microfluidic device that accurately models the tumor microenvironment, with physiologically and morphologically accurate microvasculature including leaky endothelial layers 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 will design and fabricate prototypes of plastic microfluidic chips with embedded microvascular networks. Endothelial cells and tumor cells will be cultured in these networks. The potential of this device in quantifying delivery will be assessed using two well-characterized polymers (one in clinical studies for ovarian cancer therapy). Planned Phase II enhancements include tumor-specific microvasculature and optimized methods for culturing tumor cells with endothelial cells in presence of stromal cells. Product development will be carried for volume-production and interfacing with standard imaging equipment. Custom software for data recording, analysis and storage will be developed. This product has already received enthusiastic recommendation from several potential clients/end- users. A multi-disciplinary (engineering and biology), industry-academic team with substantial expertise has been assembled for the execution of this challenging project. 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 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. 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.