Thompson C J, Tetley L, Uchegbu I F, Cheng W P
School of Pharmacy and Life Sciences, The Robert Gordon University, Schoolhill, Aberdeen, UK.
Int J Pharm. 2009 Jul 6;376(1-2):46-55. doi: 10.1016/j.ijpharm.2009.04.014. Epub 2009 Apr 16.
Novel amphiphilic polyallylamine (PAA) were previously synthesised by randomly grafting palmitoyl pendant groups and subsequent quaternising with methyl iodide. The ability of these self-assembled polymers to spontaneously form nano-complexes with insulin in pH 7.4 Tris buffer was evaluated by transmittance study, hydrodynamic size and zeta potential measurements. The transmission electron microscopy images showed that non-quaternised polymer complexes appeared to form vesicular structures at low polymer:insulin concentrations. However, at higher concentrations they formed solid dense nanoparticles. The presence of quaternary ammonium moieties resulted in insulin complexing on the surface of aggregates. All polymers exhibited high insulin complexation efficiency between 78 and 93%. Incubation with trypsin, alpha-chymotrypsin and pepsin demonstrated that most polymers were able to protect insulin against enzymatic degradation by trypsin and pepsin. Quaternised polymers appeared to have better protective effect against trypsinisation, possibly due to stronger electrostatic interaction with insulin. Interestingly, non-quaternised polymers significantly enhanced insulin degradation by alpha-chymotrypsin. All polymers were less cytotoxic than PAA, with the quaternised polymers exhibiting up to 15-fold improvement in the IC(50) value. Based on these results, quaternised palmitoyl graft polyallylamine polymers showed promising potential as oral delivery systems for insulin.
新型两亲性聚烯丙胺（PAA）先前是通过随机接枝棕榈酰侧基并随后用甲基碘进行季铵化反应合成的。通过透射率研究、流体动力学尺寸和zeta电位测量，评估了这些自组装聚合物在pH 7.4 Tris缓冲液中与胰岛素自发形成纳米复合物的能力。透射电子显微镜图像显示，在低聚合物：胰岛素浓度下，未季铵化的聚合物复合物似乎形成了囊泡结构。然而，在较高浓度下，它们形成了实心致密纳米颗粒。季铵基团的存在导致胰岛素在聚集体表面络合。所有聚合物的胰岛素络合效率都很高，在78%至93%之间。用胰蛋白酶、α-胰凝乳蛋白酶和胃蛋白酶孵育表明，大多数聚合物能够保护胰岛素免受胰蛋白酶和胃蛋白酶的酶促降解。季铵化聚合物似乎对胰蛋白酶消化具有更好的保护作用，这可能是由于与胰岛素的静电相互作用更强。有趣的是，未季铵化的聚合物显著增强了α-胰凝乳蛋白酶对胰岛素的降解作用。所有聚合物的细胞毒性均低于PAA，季铵化聚合物的IC（50）值提高了多达15倍。基于这些结果，季铵化棕榈酰接枝聚烯丙胺聚合物作为胰岛素口服给药系统显示出有前景的潜力。
