Herein, we describe a novel amphipathic chitosan derivative (N-octyl-N’-phthalyl-O-phosphoryl chitosan, abbreviated as OPPC) as an effective oral delivery platform for P-gp substrates, especially paclitaxel (PTX). OPPC could readily self-assemble into micelles, solubilize and encapsulate PTX into the hydrophobic inner core of OPPC with superior loading capacity to chitosan. PTX/OPPC micelles possessed improved intestinal epithelial permeability and oral bioavailability of PTX evaluated by in situ perfusion and pharmacokinetic studies. In vivo fluorescence imaging revealed enhanced stability and integrity of OPPC micelles in mice gastrointestine. Furthermore, cellular uptake studies revealed effective transport and accumulation of OPPC micelles loading PTX or rhodamine-123 into Caco-2 cells via clathrin/cavelin-mediated endocytosis and OPPC-mediated P-gp inhibition. Mechanistically, the inhibition of P-gp efflux pumps by OPPC resulted from the reduction of membrane fluidity and decreased P-gp ATPase activity. In summary, OPPC micelles may serve as an efficient and promising delivery system for enhancing oral bioavailability of P-gp substrates.

在这里，我们描述了一种新型的两亲性壳聚糖衍生物（N-辛基-N'-邻苯二甲酰基-O-磷酰基壳聚糖，简称为OPPC），作为P-gp底物，尤其是紫杉醇（PTX）的有效口服给药平台。OPPC可以很容易地自组装成胶束，将PTX溶解并封装到OPPC的疏水内芯中，对壳聚糖具有出色的负载能力。通过原位灌注和药代动力学研究评估，PTX / OPPC胶束具有改善的肠上皮通透性和口服生物利用度。体内荧光成像显示OPPC胶束在小鼠胃肠道中的稳定性和完整性得到增强。此外，细胞摄取研究表明，通过网格蛋白/标枪蛋白介导的内吞作用和OPPC介导的P-gp抑制作用，将PTX或若丹明123装载到Caco-2细胞中的OPPC胶束的有效转运和积累。从机理上讲，OPPC对P-gp外排泵的抑制作用是由于膜流动性降低和P-gp ATPase活性降低所致。总之，OPPC胶束可作为有效和有前途的递送系统，用于增强P-gp底物的口服生物利用度。