Thiolated Nanoparticles Overcome the Mucus Barrier and Epithelial Barrier for Oral Delivery of Insulin.,Molecular Pharmaceutics

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Thiolated Nanoparticles Overcome the Mucus Barrier and Epithelial Barrier for Oral Delivery of Insulin.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2019-12-18 , DOI: 10.1021/acs.molpharmaceut.9b00971
Shurong Zhou , Hailiang Deng , Yang Zhang , Peiyao Wu , Bing He , Wenbing Dai , Hua Zhang , Qiang Zhang , Rongsheng Zhao ₁ , Xueqing Wang

Affiliation

Oral administration is an ideal alternative for drug delivery due to its convenience and safety. However, oral protein delivery is limited by biological barriers such as the mucus barrier and epithelial barrier, which hamper drugs from entering the blood successfully. Here we presented PC6/CS NPs, a thiolated-polymer-based nanodrug delivery system in the form of poly(acrylic acid)-cysteine-6-mercaptonicotinic acid (PAA-Cys-6MNA, PC6), which is a kind of preactivated thiolated polymer, coated on chitosan (CS) nanoparticles (NPs). Its ability to overcome the mucus barrier and epithelial barrier was investigated. The existence of PC6 made the NPs prone to penetrate the mucus layer as well as strengthened the transcellular transport of insulin on epithelial cells. PC6/CS NPs efficiently enhanced the oral bioavailability of insulin to 16.2%. The improvement resulted from the function of PC6: (1) "diluting" mucus to promote nanoparticle penetration, (2) opening a tight junction to help insulin transport via the paracellular pathway, (3) making the nanoparticle more electrically neutral during the penetration process, and (4) uncoating from PC6/CS NPs so that positive CS NPs were adhered and uptaken by epithelial cells. Our study proves that PC6/CS NPs, which can achieve mucus penetration and epithelial permeation efficiently, are a potential nanocarrier for oral protein delivery.

中文翻译：

巯基化的纳米颗粒克服了胰岛素口服的粘液屏障和上皮屏障。

口服给药由于其方便性和安全性，是药物输送的理想选择。但是，口服蛋白质的输送受到诸如黏液屏障和上皮屏障等生物屏障的限制，这些屏障会阻碍药物成功进入血液。在这里，我们介绍了PC6 / CS NPs，一种基于硫醇化聚合物的纳米药物递送系统，形式为聚（丙烯酸）-半胱氨酸-6-巯基烟酸（PAA-Cys-6MNA，PC6），是一种预活化的硫醇化聚合物，包被在壳聚糖（CS）纳米颗粒（NPs）上。研究了其克服粘液屏障和上皮屏障的能力。PC6的存在使NPs易于穿透粘液层，并增强了胰岛素在上皮细胞上的跨细胞转运。PC6 / CS NP可有效提高胰岛素的口服生物利用度至16.2％。改善来自PC6的功能：（1）“稀释”粘液以促进纳米颗粒渗透，（2）打开紧密连接以帮助胰岛素通过旁细胞途径转运，（3）使纳米颗粒在渗透过程中更具电中性（4）去除PC6 / CS NP的涂层，使阳性CS NP粘附并被上皮细胞摄取。我们的研究证明，可有效实现粘液渗透和上皮渗透的PC6 / CS NPs是口服蛋白质递送的潜在纳米载体。（4）从PC6 / CS NP上脱膜，使阳性CS NP粘附并被上皮细胞摄取。我们的研究证明，可有效实现粘液渗透和上皮渗透的PC6 / CS NPs是口服蛋白质递送的潜在纳米载体。（4）从PC6 / CS NP上脱膜，使阳性CS NP粘附并被上皮细胞摄取。我们的研究证明，可有效实现粘液渗透和上皮渗透的PC6 / CS NPs是口服蛋白质递送的潜在纳米载体。

更新日期：2019-12-19

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