title: Goblet cell targeting nanoparticle containing drug-loaded micelle cores for oral delivery of insulin.
abstract: Oral administration of insulin remains a challenge due to its poor enzymatic stability and inefficient permeation across epithelium. We herein developed a novel self-assembled polyelectrolyte complex nanoparticles by coating insulin-loaded dodecylamine-graft-γ-polyglutamic acid micelles with trimethyl chitosan (TMC). The TMC material was also conjugated with a goblet cell-targeting peptide to enhance the affinity of nanoparticles with epithelium. The developed nanoparticle possessed significantly enhanced colloid stability, drug protection ability and ameliorated drug release profile compared with graft copolymer micelles or ionic crosslinked TMC nanoparticles. For in vitro evaluation, Caco-2/HT29-MTX-E12 cell co-cultures, which composed of not only enterocyte-like cells but also mucus-secreting cells and secreted mucus layer, were applied to mimic the epithelium. Intracellular uptake and transcellular permeation of encapsulated drug were greatly enhanced for NPs as compared with free insulin or micelles. Goblet cell-targeting modification further increased the affinity of NPs with epithelium with changed cellular internalization mechanism. The influence of mucus on the cell uptake was also investigated. Ex vivo performed with rat mucosal tissue demonstrated that the nanoparticle could facilitate the permeation of encapsulated insulin across the intestinal epithelium. In vivo study preformed on diabetic rats showed that the orally administered nanoparticles elicited a prolonged hypoglycemic response with relative bioavailability of 7.05%.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China; People' Hospital of Deyang City, No. 173, Northern Taishan Road, Deyang 618000, China.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Yining
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System (Ministry of Education), West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041,China. Electronic address: huangyuan0@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry; D016503:Drug Delivery Systems; D020397:Goblet Cells / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; D008823:Micelles; C118071:N-trimethyl chitosan chloride; D048271:Chitosan
keywords: CSKSSDYQC; Epithelium; Insulin; Nanoparticles; Oral delivery