Comparison of Linear and Cyclic HAV Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

• Published in: Journal of pharmaceutical sciences 2016-02, Vol.105 (2), p.797-807
• Main Authors: Alaofi, Ahmed, On, Ngoc, Kiptoo, Paul, Williams, Todd D., Miller, Donald W., Siahaan, Teruna J.
• Format: Article
• Language: English
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/S0022-3549(15)00188-4

The aim of this study is to evaluate the effect of peptide cyclization on the BBB modulatory activity and plasma stability of HAV peptides, which are derived from the EC1 domain of human E-cadherin. The activities to modulate the intercellular junctions by linear HAV4 (Ac-SHAVAS-NH 2 ), cyclic cHAVc1 (Cyclo(1,8)Ac-CSHAVASC-NH 2 ), and cyclic cHAVc3 (Cyclo(1,6)Ac-CSHAVC-NH 2 ) were compared in in vitro and in vivo BBB models. Linear HAV4 and cyclic cHAVc1 have the same junction modulatory activities as assessed by in vitro MDCK monolayer model and in-situ rat brain perfusion model. In contrast, cyclic cHAVc3 was more effective than linear HAV4 in modulating MDCK cell monolayers and in improving in vivo brain delivery of Gd-DTPA upon i.v. administration in Balb/c mice. Cyclic cHAVc3 (t 1/2 = 12.95 h) has better plasma stability compared to linear HAV4 (t 1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2–4 h) compared to HAV4 (