Effect of cationic cyclopeptides on transdermal and transmembrane delivery of insulin

Mingming Chang , Xiaohui Li , Yuming Sun , Fang Cheng , Qing Wang , Xiaohuan Xie , Weijie Zhao , and Xin Tian
Mol. Pharmaceutics, Just Accepted Manuscript
DOI: 10.1021/mp300667p
Publication Date (Web): February 7, 2013
Copyright © 2013 American Chemical Society

Poor permeability of stratum corneum limits the transportation of insulin across the skin. Transdermal peptide has exhibited enhancement activity on insulin transdermal delivery. Series cationic cyclopeptides based on the sequence of TD-1 (ACSSSPSKHCG) were designed by partial arginine or lysine scan method. Among these peptides, TD-34 (ACSSKKSKHCG) with bis-substituted lysine in N-5 and N-6 showed the best transdermal enhancement activity, the blood glucose level lower to about 26% of initial after administrating 2.1 IU insulin with 0.5 µmol TD-34 in 100 µL saline for 8h to diabetic rats in vivo. In addition, the transmembrane permeability in Caco-2 cell monolayers (BL→AP) exhibited preferable correlation with percutaneous absorption of insulin (R2 = 0.73). It can be concluded that appropriate content and position of cationic group in cyclopeptides may improve percutaneous absorption and transmembrane ability of insulin, and Caco-2 cell monolayers (BL→AP) might be applied to predict the percutaneous absorption of insulin chaperoned by a transdermal peptide in vivo.