School of Materials Science and Engineering, Center for Functional Biomaterials, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, 510275, China.
Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.
Adv Healthc Mater. 2018 Sep;7(17):e1800285. doi: 10.1002/adhm.201800285. Epub 2018 Jul 8.
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 ) 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 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 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 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.
口服递送蛋白质药物因其可重复给药且患者顺应性好而成为一种有吸引力的给药途径。然而，目前口服蛋白质治疗药物的生物利用度非常低，主要是由于存在恶劣的胃肠道（GI）环境，包括黏液层和肠上皮屏障。在此，以胰岛素作为模型蛋白质治疗药物，利用两步闪式纳米复合工艺，用巯基化透明质酸（HA-SH）涂层（NP）制备核壳纳米粒子，以提高胰岛素的口服递送效率。首先通过胰岛素和 N-(2-羟丙基）-3-三甲基氯化铵修饰壳聚糖（HTCC）之间的静电络合作用生成带正电荷的纳米粒子核，然后用 HA-SH 进行表面涂层。优化后的 NP 平均粒径为 100nm，具有较高的包封效率（91.1%）和载药量（38%）。体外和离体实验结果证实，由于 NP 的巯基化表面及其在穿过黏膜层时从纳米粒子表面解离的能力，NP 具有较高的黏液穿透能力、改善的肠道保留和跨上皮转运特性。NP 对 1 型糖尿病大鼠的口服给药具有高疗效，平均相对生物利用度为 11.3%。这些结果表明，HA-SH 涂层的核壳纳米粒子是蛋白质治疗药物有前途的口服递送载体。
