刚度效应对口服纳米药物载体克服胃肠道吸收屏障的影响及微观机制的研究

口服纳米药物载体在改善药物跨膜吸收中显现了良好的效果和前景，但前期研究主要集中于粒子尺度、表面电荷和修饰等因素对于递药效率的影响。本课题旨在探究刚度效应影响纳米药物载体克服胃肠道多重生理屏障的能力及微观机制。首先构建六个不同刚度（kPa~GPa）的药物载体，使用多粒子追踪、流式细胞仪、全内反射荧光显微镜、荧光漂白恢复等技术多维度多层次探究刚度效应对药物载体的黏液穿透、细胞摄取、胞内转运和出胞等过程的影响及效应，同时使用双光子成像等技术在动物水平上实时考察药物载体的口服吸收效率。随后，采用超高分辨显微成像等技术，从药物载体克服各生理屏障的微观动力学角度探究刚度效应对递药效率产生影响的机制机理。进一步对纳米载体的刚度优化，以期筛选出能够高效克服胃肠道多重屏障的优势刚度，为后续理性化设计高效口服纳米药物载体提供理论指导。

Nano-carriers for oral drug delivery have shown a great promise in enhancing the transmembrane absorption of drug molecules. While previous investigations primarily focus on the effects of particle size, zeta potential and surface modification. In this project, we aim to study the effects and potential mechanisms of particle rigidity on overcoming the multiple absorption barriers in the gastrointestinal tract, using nano-carriers with different rigidities (range from kPa to GPa). Technologies including multiple particle tracking, flow cytometry, total internal reflection fluorescence microscopy (TIRF) and fluorescence recovery after photobleaching (FRAP) will be employed to explore the performances of nano-carriers on mucus penetration, endocytosis, intracellular trafficking and exocytosis. Two-photon microscopy will be adopted to observe the the absorption efficiency of nano-carriers in the intestine in vivo. From the perspective of the microcosmic dynamic mechanisms underlying particle motive patterns and deformation ability during the transcytosis process, issues that how particle rigidity affects the drug-delivery efficiency will be evaluated via simulated emission depletion (STED) microscopy. In addition, the rigidity range will be further refined and optimized to obtain nano-carriers with superior absorption efficacy. This project will provide theoretical guidelines for rational design of nano-carriers to effectively overcome multiple gastrointestinal barriers.