基于肠道菌-Caco-2细胞串联培养的口服吸收屏障模型的构建及其初步应用研究

Oral delivery is the most commonly accepted route of drug administration. However, for many drugs, the oral physiological barriers impose significant limitations to their absorption, bioavailability and clinical application. To address this problem, the development of oral drug delivery systems (DDS) is very important, while the model for oral absorption barriers is a key research tool. There are multiple physiological barriers in the intestinal tract, in which gut microbiota is also an important part. According to this, the research proposes a microbe-epithelial compound intestinal barrier model based on microfluidic technology to study the in vitro performance of oral delivery system. By comparing the compound barrier model with the existing non-microbe intestinal barrier models, the study could explore the influence of gut microbiota to the intestinal absorption barrier as well as to the absorption of drug delivery systems. Furthermore, the research plans to explore the role of size, charge, shape and surface properties of oral delivery systems on the DDS-bacterium interactions, as well as their role on the final performance of oral DDS to cross the microbe-epithelial compound barrier model. Finally, the research plans to propose an optimized design strategy for oral delivery systems based on this model, and verify its performance on the compound barrier model. The study aims to enrich the library of intestinal barrier models for the research of oral drug delivery systems, and to propose strategies and information for the rational design of oral delivery systems based on the model, and finally, to provide assistance to the improvement of oral delivery efficiency.

口服给药是最常见的给药途径之一，然而大量药物难以跨越口服生理屏障，导致吸收差、生物利用度低、临床应用受限。为了提高药物的口服吸收，口服递药系统的研究十分重要，而肠道生理屏障模型则是有力的研究工具。肠道中有多重生理屏障，而肠道菌群是其重要的组成部分之一，不应忽略。基于此，拟通过微流控串联培养构建肠道菌-肠上皮新型复合生理屏障模型用于口服递药系统的体外评价，并与现有模型进行比较研究，探索肠道菌群在肠道生理屏障中的意义，及其对口服递药系统肠道吸收的影响；在此基础上，进一步考察递药系统的粒径、电位、形状、表面性质等重要性质对递药系统-肠道菌相互作用的影响，及其对递药系统跨越肠道菌-肠上皮复合生理屏障能力的影响，据此提出改良的综合设计策略并进行验证。通过本项目的研究，拟进一步丰富口服递药系统的评价模型工具库，并基于该模型为口服递药系统的合理设计提供有价值的信息，以协助进一步改善药物的口服递送效率。

口服给药是最常见的给药途径之一，然而大量药物难以跨越口服生理屏障，导致吸收差、生物利用度低、临床应用受限。为了提高药物的口服吸收，口服递药系统的研究十分重要，而肠道生理屏障模型则是有力的研究工具。肠道中有多重生理屏障，而肠道菌群是其重要的组成部分之一，不应忽略。.基于此，本研究进行了鼠李糖乳杆菌-肠上皮生理屏障模型的构建及考察；还引入了肠神经胶质细胞作为口服生理屏障的一部分，构建了肠上皮-肠神经胶质细胞生理屏障模型并进行综合考察，为后续口服递药系统的评价提供了模型和工具。.接下来，本研究进行了不同粒径、电荷、形状、表面修饰的PLGA纳米粒的处方优化、制备及表征，并以此考察了递药系统的粒径、电位、形状、表面性质等重要性质对递药系统跨越口服生理屏障能力的影响，为后续口服递药系统的综合设计提供了信息和参考。.在上述屏障模型评价工具和递药系统设计信息的基础上，本研究协助综合设计并构建了荷正电的壳寡糖包裹口服靶向脂质体，选取脊髓损伤及其消化道并发症为疾病模型，在体外口服生理屏障模型上进行了考察和优化，并在动物体内模型上进行了验证和综合评价。结果证明，该递药系统具有良好的稳定性和跨口服吸收屏障的递送能力，同时对脊髓损伤的消化系统并发症及口服吸收屏障的相关生理功能也有良好的靶向治疗、调控效果。.该研究进一步丰富了体外口服吸收生理屏障模型评价工具库，为口服递送系统的合理设计提供了信息和参考，同时对体外口服生理屏障模型的应用和生理学意义也进行了一定的、有益的扩充。