title: Enhancing insulin oral absorption by using mucoadhesive nanoparticles loaded with LMWP-linked insulin conjugates.
abstract: Although significant progress has been achieved, effective oral delivery of protein drugs such as insulin by nanoparticle-based carrier systems still faces certain formidable challenges. Considerable amount of protein drug is released from the nanoparticles (NPs) in the gastrointestinal (GI) tract. Because of their low permeability through the intestinal mucosa, the released protein would be soon degraded by the large amount of proteases in the GI tract. Herein, we report an oral insulin delivery system that can overcome the above-mentioned problems by mucoadhesive NPs (MNPs) loaded with cell penetrating peptide-linked insulin conjugates. On one hand, after conjugation with low molecular weight protamine (LMWP), a cell penetrating peptide (CPP), insulin showed greatly improved permeability through intestinal mucus layer and epithelia. On the other hand, the mucoadhesive N-trimethyl chitosan chloride-coated PLGA nanoparticles (MNPs) that were loaded with conjugates enhanced the retention in the intestinal mucus layer. By adopting this delivery strategy, the LMWP-insulin conjugates released from the MNPs could be deprived from enzymatic degradation, due to the short distance in reaching the epithelia and the high permeation of the conjugates through epithelia. The oral delivery system of insulin designed by us showed a long-lasting hypoglycemia effect with a faster onset in diabetic rats. The pharmacological availability of orally delivered conjugates-loaded MNPs was 17.98±5.61% relative to subcutaneously injected insulin solution, with a 2-fold higher improvement over that by MNPs loaded with native insulin. Our results suggested that conjugation with CPP followed by encapsulation in MNPs provides an effective strategy for oral delivery of macromolecular therapeutics.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Huining
authors.initials: H
authors.lastname: He
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Han
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Sunhui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Ru
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ruixiang
authors.initials: R
authors.lastname: Li
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: jxwang@fudan.edu.cn.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA. Electronic address: vcyang@umich.edu.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yang
mesh_terms: D000268:Adhesiveness; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D065546:Drug Liberation; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011479:Protamines / Q000008:administration & dosage* / Q000737:chemistry; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D057846:Cell-Penetrating Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; C118071:N-trimethyl chitosan chloride; D011479:Protamines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D048271:Chitosan
keywords: Cell-penetrating peptide; Insulin; Low molecular weight protamine; Mucoadhesion; Nanoparticles; Oral delivery