title: N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption.
abstract: Although several strategies have been applied for oral insulin delivery to improve insulin bioavailability, little success has been achieved. To overcome multiple barriers to oral insulin absorption simultaneously, insulin-loaded N-trimethyl chitosan chloride (TMC)-coated polylactide-co-glycoside (PLGA) nanoparticles (Ins TMC-PLGA NPs) were formulated in our study. The Ins TMC-PLGA NPs were prepared using the double-emulsion solvent evaporation method and were characterized to determine their size (247.6 ± 7.2 nm), ζ-potential (45.2 ± 4.6 mV), insulin-loading capacity (7.8 ± 0.5%) and encapsulation efficiency (47.0 ± 2.9%). The stability and insulin release of the nanoparticles in enzyme-containing simulated gastrointestinal fluids suggested that the TMC-PLGA NPs could partially protect insulin from enzymatic degradation. Compared with unmodified PLGA NPs, the positively charged TMC-PLGA NPs could improve the mucus penetration of insulin in mucus-secreting HT29-MTX cells, the cellular uptake of insulin via clathrin- or adsorption-mediated endocytosis in Caco-2 cells and the permeation of insulin across a Caco-2 cell monolayer through tight junction opening. After oral administration in mice, the TMC-PLGA NPs moved more slowly through the gastrointestinal tract compared with unmodified PLGA NPs, indicating the mucoadhesive property of the nanoparticles after TMC coating. Additionally, in pharmacological studies in diabetic rats, orally administered Ins TMC-PLGA NPs produced a stronger hypoglycemic effect, with 2-fold higher relative pharmacological availability compared with unmodified NPs. In conclusion, oral insulin absorption is improved by TMC-PLGA NPs with the multiple absorption barriers overcome simultaneously. TMC-PLGA NPs may be a promising drug delivery system for oral administration of macromolecular therapeutics.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Sheng
authors.forename: Limei
authors.initials: L
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.forename: Ge
authors.initials: G
authors.lastname: Ru
authors.forename: Ruixiang
authors.initials: R
authors.lastname: Li
authors.affiliation: ‡Department of Pharmaceutics, School of Pharmacy, Heilongjiang University of Chinese Medicine, Haerbin, Heilongjiang 150040, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Wu
authors.affiliation: ‡Department of Pharmaceutics, School of Pharmacy, Heilongjiang University of Chinese Medicine, Haerbin, Heilongjiang 150040, China.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Cui
authors.forename: Pei
authors.initials: P
authors.lastname: Yang
authors.forename: Yuwei
authors.initials: Y
authors.lastname: He
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004337:Drug Carriers; D007328:Insulin; C118071:N-trimethyl chitosan chloride; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan
keywords: N-trimethyl chitosan chloride; absorption barriers; insulin; mucus; nanoparticles; oral delivery; tight junctions