title: Enhanced stability of oral insulin in targeted peptide ligand trimethyl chitosan nanoparticles against trypsin.
abstract: Oral insulin delivery is often limited by protease degradation. 2-(Dimethylamino)-2-oxoethyl 4-(4-guanidinobenzoyloxy)phenylacetate methanesulphonate (Camostat mesylate) is reported to have the ability to inhibit trypsin activity, which is the main protease responsible for protein degradation. This study attempted to form a novel nanoparticle by covalently conjugating 4-(2-(2-aminoethylamino)-2-oxoethyl)phenyl 4-guanidinobenzoyloxy (FOY-251), an active derivative of camostat mesylate, to the backbone of poly (γ-glutamic acid) (γ-PGA), in order to improve insulin stability against protease. Goblet cell targeting CSKSSDYQC (CSK) peptide was demonstrated to effectively improve the epithelial absorption of insulin. Therefore, the novel nanoparticle was prepared by mixing cationic peptide modified trimethyl chitosan (TMC-CSK) with anionic γPGA-FOY conjugate using multi-ion crosslinked method. Results showed that not only the γPGA-FOY conjugate but also the prepared novel nanoparticle could inhibit trypsin activity both in vitro environment and on the intestinal mucosal surface. This study would be beneficial for peptide modified nanoparticles in oral insulin delivery.
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Jiexiu
authors.initials: J
authors.lastname: Chen
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shan
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Guo
authors.affiliation: a Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu , People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000201:enzymology; D008024:Ligands; D053758:Nanoparticles / Q000737:chemistry*; D011099:Polyglutamic Acid / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry*; D014361:Trypsin Inhibitors / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D004952:Esters; D006146:Guanidines; D007328:Insulin; D008024:Ligands; C118071:N-trimethyl chitosan chloride; D014361:Trypsin Inhibitors; C034532:camostat; D011099:Polyglutamic Acid; D016670:Gabexate; C045130:4-(4-guanidinobenzoyloxy)phenylacetic acid; D048271:Chitosan; D014357:Trypsin
keywords: CSKSSDYQC peptide; Camostat mesylate; TMC; Ussing chamber; insulin; oral delivery system