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

描述(由申请人提供)：我们建议开发和展示一种新的微流控装置和分析方法，用于选择和优化药物输送载体，特别是用于向肿瘤输送药物的非病毒载体。肿瘤给药是一种除药物或给药载体的物理化学性质外，还受多种因素影响的复杂现象。一个主要因素是肿瘤微血管，具有复杂的影响，包括对流血液传输，高间质压力和由于“泄漏的血管”而导致的血管通透性增加。目前的肿瘤药物体外给药模型过于简单化，结果是高估了体内的表现，预测性很差。我们建议开发一种新的微流体设备，它可以准确地模拟肿瘤微环境，具有生理和形态上准确的微血管，包括泄漏的内皮层和3D实体肿瘤。该设备将允许实时、定量地评估运送车辆在体内类似条件下的性能。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的原型。内皮细胞和肿瘤细胞将在这些网络中培养。将使用两种特性良好的聚合物(一种用于卵巢癌治疗的临床研究)来评估该设备在量化递送方面的潜力。计划中的第二阶段增强包括肿瘤特异性微血管系统和在有基质细胞存在的情况下培养肿瘤细胞和内皮细胞的优化方法。将进行产品开发，以便批量生产并与标准成像设备对接。将开发用于数据记录、分析和存储的定制软件。这一产品已经得到了几个潜在客户/最终用户的热情推荐。为了执行这一具有挑战性的项目，已经组建了一支拥有丰富专业知识的跨学科(工程学和生物学)、行业学术团队。开发的设备将在基础研究和药物发现方面都有关键应用，在基础研究中，它可以用来表征和开发下一代给药载体，在药物发现中，它可以用来研究药物在现实的肿瘤微血管网络中的疗效。该产品将向从事癌症研究和药物输送的制药/生物技术公司、药物研究实验室和大学/非营利性中心商业化。与公共卫生相关：开发的设备将在基础研究和药物发现方面都有关键应用，在基础研究中，它可以用来表征和开发下一代给药载体，在药物发现中，它可以用来研究药物在这些现实的肿瘤微血管网络中的疗效。该产品将向从事癌症研究和药物输送的制药/生物技术公司、药物研究实验室和大学/非营利性中心商业化。

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.