Multifunctional Poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-尾-cyclodextrin Amphiphilic Copolymer as an Oral High-Performance Delivery Carrier of Tacrolimus

详细信息    查看全文

• 作者：Dong Zhang ; Xiaolei Pan ; Shang Wang ; Yinglei Zhai ; Jibin Guan ; Qiang Fu ; Xiaoli Hao ; Wanpeng Qi ; Yingli Wang ; He Lian ; Xiaohong Liu ; Yongjun Wang ; Yinghua Sun ; Zhonggui He ; Jin Sun
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：July 6, 2015
• 年：2015
• 卷：12
• 期：7
• 页码：2337-2351
• 全文大小：727K
• ISSN：1543-8392

文摘

In order to improve oral bioavailability of tacrolimus (FK506), a novel poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-尾-cyclodextrin amphiphilic copolymer (CD-PVM/MA) is developed, combining the bioadhesiveness of PVM/MA, P-glycoprotein (P-gp), and cytochrome P450-inhibitory effect of CD into one. The FK506-loaded nanoparticles (CD-PVM/MA-NPs) were obtained by solvent evaporation method. The physiochemical properties and intestinal absorption mechanism of FK506-loaded CD-PVM/MA-NPs were characterized, and the pharmacokinetic behavior was investigated in rats. FK506-loaded CD-PVM/MA-NPs exhibited nanometer-sized particles of 273.7 nm, with encapsulation efficiency as high as 73.3%. FK506-loaded CD-PVM/MA-NPs maintained structural stability in the simulated gastric fluid, and about 80% FK506 was released within 24 h in the simulated intestinal fluid. The permeability of FK506 was improved dramatically by CD-PVM/MA-NPs compared to its solution, probably due to the synergistic inhibition effect of P-gp and cytochrome P450 3A (CYP3A). The intestinal biodistribution of fluorescence-labeled CD-PVM/MA-NPs confirmed its good bioadhesion to the rat intestinal wall. Two endocytosis pathways, clathrin- and caveolae-mediated endocytosis, were involved in the cellular uptake of CD-PVM/MA-NPs. The important role of lymphatic transport in nanoparticles鈥?access to the systemic circulation, about half of the contribution to oral bioavailability, was observed in mesenteric lymph duct ligated rats. The AUC_0鈥?4 of FK506 loaded in nanoparticles was enhanced up to 20-fold compared to FK506 solutions after oral administration. The present study suggested that the novel multifunctional CD-PVM/MA is a promising efficient oral delivery carrier for FK506, due to its ability in solubilization, inhibitory effects on both P-gp and CYP 3A, high bioadhesion, and sustained release capability.