School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Int J Pharm. 2021 Mar 1;596:120297. doi: 10.1016/j.ijpharm.2021.120297. Epub 2021 Jan 26.
Mucus penetration and intestinal cells targeting are two main strategies to improve insulin oral delivery efficiency. However, few studies are available regarding the effectiveness of combining these two strategies into one nano-delivery system. For this objective, the folic acid (FA) decorated virus-mimicking nanoparticles were designed and influence of FA graft ratio on the in vitro and in vivo properties of insulin loaded nanoparticles was studied systemically. Firstly, using folic acid as active ligand, different folic acid grafted chitosan copolymers (FA-CS) were synthesized and characterized. Thereafter, using insulin-loaded poly(n-butylcyanoacrylate) nanoparticles as the core, virus-mimicking nanoparticles were fabricated by coating of positively charged FA-CS copolymer and negatively charged hyaluronic acid. Irrespective of the FA graft ratio, all the nanoparticles showed good stability, similar insulin release in the gastrointestinal fluid, excellent and similar penetration in mucus. The nanoparticles permeability in intestine was FA graft ratio and segment dependent, with FA graft ratio at/over 12.51% presenting better effect in the order of duodenum > jejunum ≈ ileum. Both mechanism studies and confocal microscopy observation demonstrated FA-mediated process was involved in the transport of FA decorated nanoparticles. In vivo studies revealed hypoglycemic effect of the nanoparticles was FA graft ratio dependent, a saturation phenomenon was observed when FA graft ratio was at/over 12.51%. In conclusion, folic acid decorated virus-mimicking nanoparticles presented improved insulin absorption, implying combining mucus penetration and active transcellular transport is an effective way to promote oral insulin absorption, while the modification ratio of active ligand needs optimization.
黏液渗透和肠细胞靶向是提高胰岛素口服递送效率的两种主要策略。然而，将这两种策略结合到一个纳米递药系统中的研究很少。为此，设计了叶酸（FA）修饰的病毒模拟纳米颗粒，并系统研究了 FA 接枝率对载胰岛素纳米颗粒的体外和体内性质的影响。首先，使用叶酸作为活性配体，合成并表征了不同 FA 接枝壳聚糖共聚物（FA-CS）。此后，以载胰岛素的聚 n-丁基氰基丙烯酸酯纳米粒为核，通过带正电荷的 FA-CS 共聚物和带负电荷的透明质酸的包覆，制备了病毒模拟纳米颗粒。无论 FA 接枝率如何，所有纳米颗粒均表现出良好的稳定性、相似的胃肠液中胰岛素释放、优异且相似的黏液渗透。纳米颗粒在肠道中的通透性取决于 FA 接枝率和肠段，FA 接枝率为 12.51%或更高时，十二指肠＞空肠≈回肠的效果更好。机制研究和共聚焦显微镜观察均表明，FA 介导的过程参与了 FA 修饰纳米颗粒的转运。体内研究表明，纳米颗粒的降血糖作用取决于 FA 接枝率，当 FA 接枝率为 12.51%或更高时，出现了饱和现象。总之，叶酸修饰的病毒模拟纳米颗粒可改善胰岛素吸收，表明结合黏液渗透和主动细胞内转运是促进口服胰岛素吸收的有效方法，而活性配体的修饰比需要优化。
