基于微流控芯片技术的纳米给药系统药效学评价研究

The conventional anticancer drugs are limited by their fast metabolism, poor targeting and significant toxicity properties. Compared with these free drugs, nano-based tumor- targeting drug delivery systems (TDDS) exhibit the advantages of controlled drug release and targeting ability, which improve their bioavailability and reduced side effects. It provides a new approach for drug delivery. Up to now, the most commonly used model for TDDS screening is based on two dimensional monolayer culture, which cannot well simulate in vivo tumor microenvironment and greatly influence the accuracy and reliability of test results. In hence, there is a pressing need to develop an in vitro model to more closely mimic the tumor microenvironment for TDDS screening research. This research project is willing to synthesis novel TDDS to improve its efficacy and reduce side effects. Besides, designing an appropriate microfluidic device to construct a biomimetic in vitro tumor microenvironment which containing multicellular tumor spheroids (MTS), extracellular matrix and blood vessel for the evaluation of drug release and delivery processes. Moreover, establishment of microfluidic device with microplate reader combination system for in situ drug responses measurement on MTS and offline molecular mechanism analysis. The research project provides a novel technology platform for TDDS in vitro evaluation, which is helpful for early drug development and preclinical evaluation. It is very significant higher academic and clinical application values.

传统的抗肿瘤药物存在药物代谢速度快、特异性差、毒副作用大等缺陷，而肿瘤靶向纳米给药系统能表现出缓控释性、靶向性等优点，提高了药物的生物利用度并降低毒性，给药物输送提供新途径。但是，现阶段的体外评价模型过于简单，不能很好的模拟体内肿瘤微环境，极大影响检测结果的准确度和可靠性。因此，需要构建更接近体内肿瘤微环境模型对靶向纳米给药系统进行筛选和评价。本项目拟合成新颖的具有肿瘤靶向性的纳米给药系统，通过设计合理的微流控芯片微通道结构，构建含有肿瘤多细胞球体、细胞外基质和周围血管的肿瘤微环境体外模型，对纳米载药系统的靶向输送和可控释放性能进行研究，同时建立微流控芯片与酶标仪联用平台，对纳米给药系统的药效学进行在线评价，并利用传统分子生物学手段，探索其潜在的药物作用机制。本项目的研究成果为纳米给药系统的体外评价提供了新颖的技术平台，对药物的早期研发和临床前评价研究具有十分重要的学术意义和应用价值。

传统的抗肿瘤药物存在药物代谢速度快、特异性差、毒副作用大等缺陷，而肿瘤靶向纳米给药系统能表现出缓控释性、靶向性等优点，提高了药物的生物利用度并降低了毒性，为药物输送提供新途径。但是，现阶段药物体外评价模型过于简单，不能很好的模拟体内肿瘤微环境，极大影响检测结果的准确性和可靠性。本项目通过将肿瘤多细胞球体、细胞外基质、间隙流、氧浓度梯度和周围血管等多个与肿瘤微环境相关的因素集成到微流控芯片平台上，构建与体内微环境更接近的肿瘤模型，对纳米载药系统的靶向输送和可控释放性能进行研究，同时建立微流控芯片与酶标仪和质谱仪的联用平台，对纳米给药系统的药效学进行在线评价，并利用传统分子生物学手段，研究其潜在的药物作用机制。本项目的研究成果对纳米给药系统的体外评价提供了新的技术手段，对药物的早期研究和临床前评价具有重要的科学意义和应用价值。