title: Efficient mucus permeation and tight junction opening by dissociable "mucus-inert" agent coated trimethyl chitosan nanoparticles for oral insulin delivery.
abstract: Oral administration of protein drugs is greatly impeded by the lack of drug carriers that can efficiently overcome the absorption barriers of mucosa tissue, which consists of not only epithelium but also a blanket of mucus gel. We herein report a novel self-assembled nanoparticle (NP) platform for oral delivery of insulin by facilitating the efficient permeation through both of these two barriers. The NP possesses a core composed of insulin and trimethyl chitosan (TMC), and a dissociable "mucus-inert" hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivative. The NPs exhibited free Brownian motion and excellent permeability in mucus, which enabled the access of the NP core to the epithelial cell surface underneath the mucus. Moreover, investigation of NP behavior showed that the pHPMA molecules started to dissociate as the NP permeates through mucus, and the TMC NP core was then exposed to facilitate transepithelial transport via paracellular pathway. The pHPMA coating significantly improved transepithelial transport of TMC-based NP and their ability to open tight junctions between the mucus-secreting epithelial cells. Moreover, in diabetic rats, pHPMA coated NPs generated a prominent hypoglycemic response following oral administration, and exhibited a relative bioavailability 2.8-fold higher than that of uncoated TMC-based NPs. Our study provided the evidence of using pHPMA as "mucus-inert" agent to enhance mucus permeation of TMC-based NPs, and validated a novel strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and TMC-based core possessing tight junction-opening ability.
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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Jian
authors.initials: J
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, South Renmin Road, Chengdu 610041, PR 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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shan
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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Jiaju
authors.initials: J
authors.lastname: Zhong
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, South Renmin Road, Chengdu 610041, PR China.
authors.forename: Zhirong
authors.initials: Z
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, South Renmin Road, Chengdu 610041, PR China. Electronic address: huangyuan0@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D048271:Chitosan / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D065546:Drug Liberation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009093:Mucus / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010539:Permeability; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000378:metabolism
chemical_list: D000178:Acrylamides; D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; C118071:N-trimethyl chitosan chloride; D048271:Chitosan; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: HPMA copolymers; Insulin; Mucus layer; Nanoparticles; Oral delivery; Trimethyl chitosan