智能黏膜穿透纳米马达载药系统的设计及其调控与强化

The mucus layer in the mucosal system seriously limits the diffusion and endocytosis of the gene/drug into the mucosal epithelium and poses difficulties in mucosal drug delivery system. This project, aiming at the mass transfer differences in the two key processes of mucosal drug delivery, which needs to penetrate mucus and then to be endocytosed by the mucosal epithelial cells, proposed the design of the smart mucosal penetrating nanomotor for drug delivery: with the smart groups on its surface, the neutral muco-inert surface which benefits the diffusion in mucus layer would change towards the positively charged surface which is favor to the endocytosis. Moreover, with the combination of the nanomotor as its core and ultrasonic, the superposition of multiple strengthening effects on the mass transfer and the reaction process will be achieved, finally improving the therapeutic efficiency of mucosal drug delivery system. This project intends to investigate the effect of zwitterionic polymer surface modification (muco-inerting), the effect of acid-sensitive group modification (intelligence), the effect of nanomotor driven, onto the diffusion and endocytosis of nanoparticles in the mucosal system, through diffusion, endocytosis experiments combined with molecular dynamics simulation. Then the regulation and intensification mechanism of above muco-inerting, intelligence, and nanomotor driven would be analyzed, and the structure of the carrier affording the coordination of key function of each component in the drug delivery system will be optimized, thus the design scheme of smart mucosal penetrating nanoparticle will be established. This project will provide new ideas for mucosal drug delivery design and extend of the application of process intensification in gene/drug carriers.

黏膜系统中的黏液层会阻碍基因/药物的有效扩散和吸收，为黏膜给药带来困难。本项目针对黏膜给药所需实现的穿透黏液屏障层和进入黏膜上皮细胞这两个关键过程的传质特性差异，提出了研制智能黏膜穿透纳米马达的研究构想：首先在载药粒子表面引入智能分子基团，使其可从有利于黏液层传质的惰性表面向有利于跨膜传质的正电荷表面转变；其次在载体中嵌入纳米马达，利用超声驱动马达实现对药物传递和药物反应过程的多重强化，显著提高黏膜给药治疗效率。拟构建两性离子聚合物惰性化修饰和酸敏感基团智能化修饰表面、内部嵌入纳米马达的载药粒子，研究黏液扩散和细胞摄取特性，结合分子动力学模拟，研究载药系统的黏液层传质和跨膜传质行为，解析惰性化、智能化和马达驱动的调控和强化机理，优化载药系统中各组分协调作用的载体结构，建立“智能黏膜穿透”载药系统的设计方案，为黏膜给药系统设计提供新思路，开拓过程强化在基因/药物载体中的新应用。

机体黏膜系统中的黏液屏障会阻碍药物的有效扩散和吸收，为黏膜给药带来困难。因此，本项目针对黏膜给药所需实现的穿透黏液屏障层和进入黏膜上皮细胞这两个关键过程的传质特性差异，构建了两性离子聚合物惰性化修饰表面、酸敏感基团智能化修饰表面、内部引入磁场驱动以及近红外驱动纳米马达的新型跨黏膜给药载药粒子，系统研究了载药粒子在黏液层和黏膜细胞中的扩散行为、响应性、细胞毒性、细胞摄取等特性，获得了多种快速透黏液层并高效进入黏膜上皮细胞的新型的“智能黏膜穿透”微纳米载体，例如JMSNs-pCBMA、Janus-MMSN-pCB、MSNs-pCBMA-DMMA等。在此基础上，本项目通过解析惰性化、智能化和马达驱动的调控和强化机理，对载药系统中各组分协调作用的载体结构进行了优化设计，最终确认了载药粒子中各组分功能可协调发挥作用的载体结构及其特征参数，并建立了“智能黏膜穿透”载药系统的设计方案：表面惰性化是必要基础，不但有利于黏液层穿透同时还降低了细胞毒性；马达驱动是关键调控因素，虽大幅度提升传质和跨膜效率，但会增加细胞毒性，因此需要精准调控外场强度和作用时间；表面智能化须基于惰性化修饰，可以进一步提升跨黏膜效率。本项目研究成果为跨黏膜给药系统设计提供了理论基础和技术支持，并为过程强化在药物载体中的应用奠定基础。