title: Multifunctional Poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-β-cyclodextrin Amphiphilic Copolymer as an Oral High-Performance Delivery Carrier of Tacrolimus.
abstract: In order to improve oral bioavailability of tacrolimus (FK506), a novel poly(methyl vinyl ether-co-maleic anhydride)-graft-hydroxypropyl-β-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' access to the systemic circulation, about half of the contribution to oral bioavailability, was observed in mesenteric lymph duct ligated rats. The AUC0-24 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.
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.|‡Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia 23284-2526, United States.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Pan
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Shang
authors.initials: S
authors.lastname: Wang
authors.affiliation: ∥School of Medical Devices, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yinglei
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Guan
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Hao
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Wanpeng
authors.initials: W
authors.lastname: Qi
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ∥School of Medical Devices, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: He
authors.initials: H
authors.lastname: Lian
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Sun
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
authors.affiliation: †Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.|⊥Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D008297:Male; D008298:Maleates / Q000737:chemistry*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010316:Particle Size; D011095:Polyethylenes / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D008298:Maleates; D011095:Polyethylenes; D011108:Polymers; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C043105:poly(methyl vinyl ether-co-maleic anhydride); D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP 3A; P-gp; bioavailability; nanoparticles; tacrolimus (FK506)