基于肠道氨基酸吸收途径的口服纳米递药系统构建及其跨细胞转运的研究

Surface modification of specific ligands can promote the cellular uptake of nanoparticles, leading to the enhanced oral absorption of loaded drugs. Though the cellular uptake of nanoparticles can be enhanced to some extent, endocytosed nanoparticles are faced with complex intracellular transport, thus only a small part of the nanoparitcles achieves the basolateral exocytosis. This phenomenon is called the contradiction of “easy uptake hard transcytosis”. Therefore, the construction of nanoparticles with high transcytosis efficiency, which could avoid the above contradiction, to promote the oral bioavailability of the loaded drug, is still an urgent problem in the study of oral drug delivery system. Based on current researches, in this project, we plan to synthesize a series of amphiphilic dendrimer using dendritic polylysine as the backbone, which then takes part in the assembly of nanoparticles with amino-acid-like surface property. These nanoparticles are expected to hold a well affinity with the cell membrane, as well as an enhanced basolateral exocytosis through the interaction with amino acid transporters, which may further lead to an increased endocytosis. In this project, we will study the preparation, stability, the cellular uptake and the transcytosis of the designed nanoparticles systemically, thus to obtain a novel oral nano delivery system with high transcellular transport ability.

尽管通过特定配体修饰等策略能显著增加纳米粒的肠上皮细胞摄取，最终从基底侧出胞的纳米粒却难有相似程度的增加，即“入胞容易，出胞难”的矛盾。因此，如何有效避免此矛盾，构建具有较强跨细胞转运能力的纳米粒，进一步提高所载药物的口服生物利用度，仍是目前口服递药系统研究中亟待解决的问题。在现有研究基础上，本项目拟以分枝状聚赖氨酸为骨架，设计合成一系列两亲性分枝状大分子，并参与组装得到具有氨基酸类表面特征的纳米粒。期望该纳米粒能保持分枝状聚赖氨酸骨架与细胞膜亲和力，具有较好细胞摄取的同时，能通过与细胞基底侧氨基酸转运体的相互结合，促进该纳米粒基底侧出胞，进一步增强跨细胞转运效率。本项目将系统的研究该纳米粒的制备工艺、细胞摄取与跨细胞转运能力等，从而获得能高效跨细胞转运的新型口服纳米递药系统。同时，本项目还将对该类纳米粒的胞内转运途径与相关机制进行系统的研究，为口服纳米递药系统的合理设计提供理论参考。

围绕纳米粒“入胞容易出胞难”的问题，本项目的研究从纳米粒的表面性质入手，设计并构建了两种纳米粒：①具有树状寡肽表面结构特征的纳米粒；②具备半胱氨酸及聚精氨酸表面修饰的纳米粒。项目研究过程中，对上述两种纳米粒分别进行了跨细胞转运相关研究以及动物体内递药相关研究。结果表明，具备树状寡肽表面特征的纳米粒能通过氨基酸相关转运途径实现跨细胞转运，增加所载药物的口服吸收。另一方面，纳米粒表面的半胱氨酸修饰有助于被摄取进入细胞的纳米粒避开溶酶体，通过内质网高尔基体途径出胞。结合聚精氨酸促进纳米粒细胞摄取的作用，将有助于纳米粒实现高效的跨细胞转运，从而增加所载药物的口服吸收。通过本项目的研究结果，我们可以推测表面具备氨基酸结构特征的纳米粒在口服递药中具备较大潜力。本项目的研究将为进一步研究提供有效的参考。. 本项目的研究按计划完成，研究内容已发表SCI论文2篇。