Uniform Core–Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin,Advanced Healthcare Materials

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Uniform Core–Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2018-07-08 , DOI: 10.1002/adhm.201800285
Houkuan Tian ₁ , Zhiyu He ₁ , Chengxin Sun ₁ , Chengbiao Yang ₁ , Pengfei Zhao ₁ , Lixin Liu ₁ , Kam W. Leong _{1,

2} , Hai-Quan Mao _{1,

3,

4} , Zhijia Liu ₁ , Yongming Chen ₁

Affiliation

Oral delivery of protein drugs is an attractive route of administration due to its convenience for repeated dosing and good patient compliance. However, currently oral protein therapeutics show very low bioavailability mainly due to the existence of hostile gastrointestinal (GI) environments, including mucus layers and intestinal epithelial barriers. Herein, using insulin as a model protein therapeutic, the core–shell nanoparticles with thiolated hyaluronic acid (HA‐SH) coating (NP_HA‐SH) are produced utilizing a two‐step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and N‐(2‐hydroxypropyl)‐3‐trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA‐SH. The optimized NP_HA‐SH shows an average size of 100 nm with high encapsulation efficiency (91.1%) and loading capacity (38%). In vitro and ex vivo results confirm that NP_HA‐SH shows high mucus‐penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA‐SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NP_HA‐SH to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA‐SH coated core–shell nanoparticles are a promising oral delivery vehicle for protein therapeutics.

中文翻译：

均一的核壳纳米粒子，带有硫羟透明质酸涂层，可增强胰岛素的口服传递

蛋白质药物的口服给药是一种有吸引力的给药途径，因为它便于重复给药和良好的患者依从性。然而，当前的口服蛋白质治疗剂显示出非常低的生物利用度，这主要是由于存在敌对的胃肠道（GI）环境，包括粘液层和肠上皮屏障。在此，以胰岛素为模型蛋白治疗剂，采用两步快速纳米复合工艺制备了具有巯基化透明质酸（HA-SH）涂层（NP _HA-SH）的核壳纳米颗粒，以提高胰岛素的口服递送效率。带正电的纳米颗粒核首先通过胰岛素与N之间的静电络合生成-（2-羟丙基）-3-三甲基氯化铵改性壳聚糖（HTCC），然后用HA-SH进行表面涂层。经过优化的NP _HA-SH的平均尺寸为100 nm，具有高封装效率（91.1％）和负载能力（38％）。体外和离体结果证实，NP _HA‐SH具有高的粘液穿透能力，改善的肠道保留能力和上皮转运特性，这归因于其硫醇化表面以及HA–SH涂层穿过粘膜层时从纳米颗粒表面解离的能力。。NP _HA‐SH的口服对1型糖尿病大鼠的治疗具有很高的疗效，平均相对生物利用度为11.3％。这些结果表明，HA-SH包被的核-壳纳米颗粒是用于蛋白质治疗的有前途的口服载体。

更新日期：2018-07-08

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