Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
J Control Release. 2016 Jul 10;233:181-90. doi: 10.1016/j.jconrel.2016.05.015. Epub 2016 May 10.
Although significant progress has been achieved, effective oral delivery of protein drugs such as insulin by nanoparticle-based carrier systems still faces certain formidable challenges. Considerable amount of protein drug is released from the nanoparticles (NPs) in the gastrointestinal (GI) tract. Because of their low permeability through the intestinal mucosa, the released protein would be soon degraded by the large amount of proteases in the GI tract. Herein, we report an oral insulin delivery system that can overcome the above-mentioned problems by mucoadhesive NPs (MNPs) loaded with cell penetrating peptide-linked insulin conjugates. On one hand, after conjugation with low molecular weight protamine (LMWP), a cell penetrating peptide (CPP), insulin showed greatly improved permeability through intestinal mucus layer and epithelia. On the other hand, the mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles (MNPs) that were loaded with conjugates enhanced the retention in the intestinal mucus layer. By adopting this delivery strategy, the LMWP-insulin conjugates released from the MNPs could be deprived from enzymatic degradation, due to the short distance in reaching the epithelia and the high permeation of the conjugates through epithelia. The oral delivery system of insulin designed by us showed a long-lasting hypoglycemia effect with a faster onset in diabetic rats. The pharmacological availability of orally delivered conjugates-loaded MNPs was 17.98±5.61% relative to subcutaneously injected insulin solution, with a 2-fold higher improvement over that by MNPs loaded with native insulin. Our results suggested that conjugation with CPP followed by encapsulation in MNPs provides an effective strategy for oral delivery of macromolecular therapeutics.
尽管已经取得了重大进展，但通过基于纳米粒子的载体系统将蛋白质药物（如胰岛素）有效递送至口服途径仍面临着一定的挑战。大量的蛋白质药物会从胃肠道（GI）中的纳米粒子（NPs）中释放出来。由于其通过肠黏膜的通透性较低，释放的蛋白质很快会被 GI 道中大量的蛋白酶降解。在此，我们报告了一种口服胰岛素递送系统，该系统可以通过负载细胞穿透肽连接胰岛素缀合物的黏膜黏附纳米粒子（MNPs）来克服上述问题。一方面，与低分子量鱼精蛋白（LMWP）缀合后，细胞穿透肽（CPP）使胰岛素的通透性大大提高，穿过肠黏液层和上皮细胞。另一方面，负载缀合物的带正电荷的 N-三甲基壳聚糖盐酸盐涂层的 PLGA 纳米粒子（MNPs）增强了在肠黏液层中的保留。通过采用这种递药策略，MNPs 释放的 LMWP-胰岛素缀合物由于到达上皮细胞的距离较短以及缀合物通过上皮细胞的高渗透性而免受酶降解。我们设计的胰岛素口服递送系统在糖尿病大鼠中表现出持久的降血糖作用，起效更快。与皮下注射胰岛素溶液相比，MNPs 负载缀合物的口服生物利用度为 17.98±5.61%，相对于 MNPs 负载天然胰岛素提高了 2 倍。我们的结果表明，CPP 缀合后再包封在 MNPs 中为大分子治疗药物的口服递药提供了一种有效的策略。
