title: Uptake, transport and peroral absorption of fatty glyceride grafted chitosan copolymer-enoxaparin nanocomplexes: influence of glyceride chain length.
abstract: The objective of this paper is to elucidate the influence of fatty glyceride chain length in chitosan copolymers on the peroral absorption of enoxaparin. First of all, a series of chitosan copolymers with glyceryl monocaprylate (GM8), glyceryl monolaurate (GM12) and glyceryl monostearate (GM18) as the hydrophobic part were synthesized. The structure of the copolymers was characterized using proton nuclear magnetic resonance. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that all the copolymers were non-toxic. Enoxaparin nanocomplexes were prepared by self-assembly. Mucoadhesion of the nanocomplexes was characterized using the mucin particle method. Nanocomplex uptake and transport were quantified in Caco-2 cells and cellular localization was visualized by confocal laser scanning microscopy. Enoxaparin uptake was enhanced by nanocomplex formation, and was dependent on incubation time, concentration, temperature and glyceride chain length. The GM8 grafted chitosan-enoxaparin nanocomplex exhibited the strongest bioadhesion and the best uptake and transport in both cell culture and in vivo absorption in rats. The uptake mechanism was assumed to be adsorptive endocytosis via clathrin- and caveolae-mediated processes. In conclusion, oral absorption of enoxaparin can be further enhanced by using GM8 grafted chitosan copolymer as the carrier to form nanocomplexes.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Chenjun
authors.initials: C
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Xiaopin
authors.initials: X
authors.lastname: Duan
authors.affiliation: Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: maoshirui@syphu.edu.cn.
authors.forename: Shirui
authors.initials: S
authors.lastname: Mao
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry*; D004058:Diffusion; D017984:Enoxaparin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005989:Glycerides / Q000737:chemistry*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D053761:Nanocomposites / Q000737:chemistry / Q000648:ultrastructure; D065568:Oral Mucosal Absorption / Q000502:physiology*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D005989:Glycerides; D053769:Nanocapsules; D048271:Chitosan
keywords: Chitosan; Enoxaparin; Fatty glyceride; Oral; Polyelectrolyte nanocomplexes