Synthesis of CSK-DEX-PLGA Nanoparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Absorption,Molecular Pharmaceutics

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Synthesis of CSK-DEX-PLGA Nanoparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Absorption
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-01-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00809
Yina Song ₁ , Yanan Shi ₂ , Liping Zhang ₁ , Haiyan Hu ₁ , Chunyan Zhang ₁ , Miaomiao Yin ₁ , Liuxiang Chu ₁ , Xiuju Yan ₁ , Mingyu Zhao ₁ , Xuemei Zhang ₃ , Hongjie Mu ₁ , Kaoxiang Sun _{1,

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Affiliation

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.

中文翻译：

用于口服艾塞那肽的CSK-DEX-PLGA纳米粒子的合成，以改善其粘液渗透和肠道吸收。

艾塞那肽（一种用于治疗2型糖尿病的药物）的口服吸收可通过使用纳米颗粒（NPs）来改善其吸收。为了提高艾塞那肽的粘液渗透和肠道吸收，我们设计了一种嵌段共聚物CSKSSDYQC-葡聚糖-乳酸-乙醇酸共聚物（CSK-DEX-PLGA），并将其用于制备塞有艾塞那肽的NP。由CSK-DEX-PLGA组成的功能化装载艾塞那肽的NP能够靶向肠上皮细胞并降低肠的粘液阻滞作用。此外，基于肠环的体外结扎和检查不同的肠吸收位点，发现DEX-PLGA的CSK修饰可显着提高小肠中NP的吸收效率。与DEX-PLGA-NP（DP）相比，绒毛中CSK-DEX-PLGA-NP（CDP）的吸收增加，从而使该药物通过网格蛋白，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，在对Caco-2 / HT-29-MTX共培养细胞的研究中，观察到CDP的转运能力增强。糖尿病大鼠口服后，CDPs表现出延长的降血糖反应，相对生物利用度为9.2％。总之，CDP可以靶向小肠杯状细胞，并且对作为纳米级载体的大分子肽的口服给药具有有益的作用。糖尿病大鼠口服后，CDPs表现出延长的降血糖反应，相对生物利用度为9.2％。总之，CDP可以靶向小肠杯状细胞，并且对作为纳米级载体的大分子肽的口服给药具有有益的作用。糖尿病大鼠口服后，CDPs表现出延长的降血糖反应，相对生物利用度为9.2％。总之，CDP可以靶向小肠杯状细胞，并且对作为纳米级载体的大分子肽的口服给药具有有益的作用。

更新日期：2019-01-02

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