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。一个关键因素是肿瘤微血管，它具有复杂的效应，包括对流传输、高间质压力和由于“泄漏血管”的存在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，其结果是与体内表现的相关性很差。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，包括内皮细胞衬里的泄漏毛细血管和3D实体肿瘤。该设备将允许实时、定量地评估运载工具在体内类似条件下的性能。在第一阶段，我们设计并制造了嵌入有泄漏间隙的微血管网络的塑料微流控芯片的原型。血管内皮细胞和宫颈肿瘤细胞的3D球体在网络中共培养。利用基因递送纳米聚合物成功地进行了药物载体的筛选。计划中的第二阶段改进包括优化渗漏的血管系统，以及扩展用于培养乳腺、卵巢和肺肿瘤细胞的设备。将研究微流控装置筛选药物载体的能力，筛选靶向药物传递，以及除了基因传递外，颗粒形状对传递的作用。为了成功实施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，它可以用来开发下一代给药载体，在现实肿瘤微环境中，它可以用来研究药物疗效。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 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.