School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong , Yantai University , Yantai 264005 , China.
School of Pharmacy , Binzhou Medical University , Yantai 264005 , China.
Mol Pharm. 2019 Feb 4;16(2):518-532. doi: 10.1021/acs.molpharmaceut.8b00809. Epub 2019 Jan 14.
The oral absorption of exenatide, a drug for type 2 diabetes treatment, can be improved by using nanoparticles (NPs) for its delivery. To improve the mucus penetration and intestinal absorption of exenatide, we designed a block copolymer, CSKSSDYQC-dextran-poly(lactic-co-glycolic acid) (CSK-DEX-PLGA), and used it for the preparation of exenatide-loaded NPs. The functionalized exenatide-loaded NPs composed of CSK-DEX-PLGA were able to target intestinal epithelial cells and reduce the mucus-blocking effect of the intestine. Moreover, the CSK modification of DEX-PLGA was found to significantly promote the absorption efficiency of NPs in the small intestine based on in vitro ligation of the intestinal rings and an examination of different intestinal absorption sites. Compared to DEX-PLGA-NPs (DPs), the absorption of CSK-DEX-PLGA-NPs (CDPs) was increased in the villi, allowing the drug to act on gobletlike Caco-2 cells through clathrin-, caveolin-, and gap-mediated endocytosis. Furthermore, the enhanced transport ability of CDPs was observed in a study on Caco-2/HT-29-MTX cocultured cells. CDPs exhibited a prolonged hypoglycemic response with a relative bioavailability of 9.2% in diabetic rats after oral administration. In conclusion, CDPs can target small intestinal goblet cells and have a beneficial effect on the oral administration of macromolecular peptides as a nanometer-sized carrier.
用于 2 型糖尿病治疗的药物艾塞那肽的口服吸收可以通过使用纳米颗粒（NPs）来提高其递送效率。为了提高艾塞那肽的黏液穿透和肠道吸收能力，我们设计了一种嵌段共聚物 CSKSSDYQC-葡聚糖-聚（乳酸-共-乙醇酸）（CSK-DEX-PLGA），并将其用于制备载艾塞那肽的 NPs。由 CSK-DEX-PLGA 组成的功能化载艾塞那肽 NPs 能够靶向肠道上皮细胞并减少肠道的黏液阻塞作用。此外，发现 DEX-PLGA 上的 CSK 修饰可显著提高 NPs 在小肠中的吸收效率，这是基于对肠环的体外连接和对不同肠道吸收部位的检查。与 DEX-PLGA-NPs（DPs）相比，CSK-DEX-PLGA-NPs（CDPs）在绒毛中的吸收增加，使药物能够通过网格蛋白、小窝蛋白和间隙介导的内吞作用作用于杯状 Caco-2 细胞。此外，在 Caco-2/HT-29-MTX 共培养细胞的研究中观察到 CDPs 的增强转运能力。在糖尿病大鼠口服给药后，CDPs 表现出延长的降血糖反应，相对生物利用度为 9.2%。总之，CDPs 可以靶向小肠杯状细胞，并作为纳米级载体对大分子肽的口服给药具有有益作用。
