title: Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery.
abstract: Trimethyl chitosan-cysteine conjugate (TMC-Cys) was synthesized in an attempt to combine the mucoadhesion and the permeation enhancing effects of TMC and thiolated polymers related to different mechanisms for oral absorption. TMC-Cys with various molecular weights (30, 200, and 500 kDa) and quaternization degrees (15 and 30%) was allowed to form polyelectrolyte nanoparticles with insulin through self-assembly, which demonstrated particle size of 100-200 nm, zeta potential of +12 to +18 mV, and high encapsulation efficiency. TMC-Cys/insulin nanoparticles (TMC-Cys NP) showed a 2.1-4.7-fold increase in mucoadhesion compared to TMC/insulin nanoparticles (TMC NP), which might be partly attributed to disulfide formation between TMC-Cys and mucin as evidenced by DSC measurement. Compared to insulin solution and TMC NP, TMC-Cys NP induced increased insulin transport through rat intestine by 3.3-11.7 and 1.7-2.6 folds, promoted Caco-2 cell internalization by 7.5-12.7 and 1.7-3.0 folds, and augmented uptake in Peyer's patches by 14.7-20.9 and 1.7-5.0 folds, respectively. Such results were further confirmed by in vivo experiment with the optimal TMC-Cys NP. Biocompatibility assessment revealed lack of toxicity of TMC-Cys NP. Therefore, self-assembled nanoparticles between TMC-Cys and protein drugs could be an effective and safe oral delivery system.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Lichen
authors.initials: L
authors.lastname: Yin
authors.forename: Jieying
authors.initials: J
authors.lastname: Ding
authors.forename: Chunbai
authors.initials: C
authors.lastname: He
authors.forename: Liming
authors.initials: L
authors.lastname: Cui
authors.forename: Cui
authors.initials: C
authors.lastname: Tang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yin
mesh_terms: D000268:Adhesiveness; D000284:Administration, Oral; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry*; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000737:chemistry*; D008422:Materials Testing; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use / Q000648:ultrastructure; D010316:Particle Size; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D007328:Insulin; D013438:Sulfhydryl Compounds; D048271:Chitosan