基于上皮细胞BL侧转运蛋白底物前药的设计及载前药智能化纳米载体促口服吸收机制的研究

The gastrointestinal epithelial-cell barrier is one of the most important barrier for oral drug absorption. The transport proteins which asymmetrically distributed in apical brush border membrane (AP) and basolateral (BL) membrane of epithelial-cell play an important role in drug absorption. This project focuses on designing a novel drug delivery system for overcoming the intestinal epithelial-cell barrier of BCS IV drugs. The novel drug delivery system will be designed including a prodrug which modifed by a small peptide obtained by computer aided drug design and high throughput bioscreening techniques. The prodrug can be served as a substrate for MRP3, a transporter highly expresses on the bilateral side of epithelial-cell and can faciliteate transmembrane transport of the substrate.A novel nanocarrier is also designed to efficiently intracellular deliver of the prodrug. When the nanocarrier enters into cell lysosome, it can be fast dissolved in the acidic environment, quickly releasing the prodrug. The released prodrug molecules can be transported through BL side of cell membrane mediated by MRP3 and enter into the circulation system, significantly improving the drug absorpiton. By studying the biological fate of this novel drug delivery system using a series of microscopic visualization techniques, our findings will dramatically advance our understanding of improving the oral absorption of BCS IV drugs.

消化道上皮细胞屏障是药物口服吸收最重要的屏障之一，其刷状缘顶膜侧（AP侧）和基底侧（BL侧）不对称性分布的转运蛋白对于药物的吸收和转运发挥着重要的作用。本课题首次基于肠上皮细胞BL侧特异性高表达的MRP3介导底物药物向血管侧单向转运的机制，通过计算机辅助设计和细胞筛选相结合的方法，筛选合成MRP3特异性底物小肽修饰的前体药物。同时，通过配基修饰的智能型核壳组装体（Lip-CaP-MN）包载前体药物，利用该载体实现高效入胞和pH触发式释药的效应，促使肠上皮细胞内高浓度的前体药物经由BL侧的MRP3介导转运至血液循环中， 显著提高低吸收的BCS IV类药物的生物利用度。此外，还将载体的设计制备与分子影像技术相结合，对载体在上皮细胞内的命运和运转过程进行可视化监控，以期为低吸收药物提供有效的促吸收策略。

受小肠极性上皮细胞顶侧和基底侧膜屏障以及顶侧膜蛋白P-gp的外排作用限制，大部分抗癌药物的口服递送难以实现。另外。本项目研究开发一种纳米载体结合功能性前体药物的递药手段，显著性提高了药物的跨肠细胞顶/基底侧膜的能力，避免了P-gp外排，实现了体内母体药物的快速释放，进而提高了药物的口服生物利用度。本项目以低渗透性药物盐酸多柔比星为模型药物，修饰以葡糖醛酸酯基团，并装载于磷酸钙纳米粒。纳米载体的应用促进了前体药物的顶侧膜摄取入胞，而葡糖醛酸酯基团，促使低渗透药物分子选择性经基底侧膜蛋白MRPs的转运出胞入血，而非经顶侧膜蛋白P-gp的外排。相对于盐酸多柔比星溶液，药物的跨肠细胞极性细胞单层的转运效率提高了5.83倍，口服生物利用度提高至11.85倍。这一口服递送手段为低渗透性药物的口服递送提高了一种全新的方法，也为前体药物的发展提供了更广阔的视野。

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