title: Oligoarginine-modified biodegradable nanoparticles improve the intestinal absorption of insulin.
abstract: The strategy of oral administration of bioactive macromolecules using cell-penetrating peptides (CPPs) is restricted to covalent linkage or electrostatic interaction between the cargo and CPPs. In the present study, we devised an approach utilizing CPP-functionalized poly(lactic-co-glycolic acid) (PLGA) nanoparticles as a carrier for oral delivery of insulin. Pegylated PLGA nanoparticles were modified with poly(arginine)8 enantiomers (l-R8 and d-R8) via a maleimide-mediated covalent conjugating procedure. The physical and chemical features of the nanoparticles were characterized, which confirmed the successful immobilization of R8 to the nanoparticles. Using a Caco-2 cell monolayer model, R8-modified nanoparticles were found to exhibit significantly increased cellular uptake and transportation. Pharmacokinetics and pharmacodynamics of the insulin-loaded nanoparticles were evaluated with rats by intestinal administration. Compared to the unmodified nanoparticles, l-R8 and d-R8 modified-nanoparticles increased the relative bioavailabilities of insulin by 3.2- and 4.4-times, meanwhile, improved the hypoglycemic effects by 2.5- and 3.7-times, respectively. Neither of the R8-modified nanoparticles caused perceptible histological toxicities. The results implied that surface modification of biodegradable nanoparticles with poly(arginine)8, especially with the d-form enantiomer, showed remarkable advancement in promoting the intestinal absorption of insulin. This delivery system is also promising for the delivery of a wide variety of bioactive macromolecules by oral administration.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Wenjian
authors.initials: W
authors.lastname: Zhang
authors.forename: Cao
authors.initials: C
authors.lastname: Xie
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D007408:Intestinal Absorption; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D001786:Blood Glucose; D057846:Cell-Penetrating Peptides; D003374:Coumarins; D007328:Insulin; D009842:Oligopeptides; D013844:Thiazoles; C517282:coumarin 6; C500307:octa-arginine peptide; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D007770:L-Lactate Dehydrogenase