title: Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport.
abstract: The present study was to demonstrate the effects of goblet cell-targeting nanoparticles on the oral absorption of insulin in vitro, ex vivo and in vivo, and identify the targeting mechanism as well as the influence of mucus. The insulin loaded nanoparticles were prepared using trimethyl chitosan chloride (TMC) modified with a CSKSSDYQC (CSK) targeting peptide. Compared with unmodified nanoparticles, the CSK peptide modification could facilitate the uptake of nanoparticles in villi, enhance the permeation of drugs across the epithelium, meanwhile, induce a significantly higher internalization of drugs via clathrin and caveolae mediated endocytosis on goblet cell-like HT29-MTX cells. In transport studies across Caco-2/HT29-MTX co-cultured cell monolayer (simulating intestinal epithelium), the CSK peptide modification also showed enhanced transport ability, even if the targeting recognition was partially affected by mucus. Moreover, it was found the existence of mucus was propitious to the transport of insulin from both modified and unmodified nanoparticles. In the pharmacological and pharmacokinetic studies in diabetic rats, the orally administrated CSK peptide modified nanoparticles produced a better hypoglycemic effect with a 1.5-fold higher relative bioavailability compared with unmodified ones. In conclusion, CSK peptide modified TMC nanoparticles showed sufficient effectiveness as goblet cell-targeting nanocarriers for oral delivery of insulin.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Jin
authors.forename: Yupin
authors.initials: Y
authors.lastname: Song
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Chunhui
authors.initials: C
authors.lastname: Chen
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects; D048271:Chitosan / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods*; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009093:Mucus / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C118071:N-trimethyl chitosan chloride; D010455:Peptides; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate