期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 105, 期 2, 页码 797-807出版社
WILEY
DOI: 10.1016/S0022-3549(15)00188-4
关键词
blood-brain barrier; BBB; brain delivery; cadherin peptides; HAV peptide; paracellular pathway; tight junction; adherens junction; BBB modulation
资金
- National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) [R01-NS075374]
The aim of this study is to evaluate the effect of peptide cyclization on the blood-brain barrier (BBB) modulatory activity and plasma stability of His-Ala-Val peptides, which are derived from the extracellular 1 domain of human E-cadherin. The activities to modulate the intercellular junctions by linear HAV4 (Ac-SHAVAS-NH2), cyclic cHAVc1 (Cyclo(1,8) Ac-CSHAVASC-NH2), and cyclic cHAVc3 (Cyclo(1,6)Ac-CSHAVC-NH2) 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 on i.v. administration in Balb/c mice. Cyclic cHAVc3 (t(1/2) = 12.95 h) has better plasma stability compared with linear HAV4 (t(1/2) = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2-4 h) compared with HAV4 (<1 h). Both HAV4 and cHAVc3 peptides also enhanced the in vivo brain delivery of IRdye800cw-PEG (25 kDa) as detected by near IR imaging. The result showed that cyclic cHAVc3 peptide had better activity and plasma stability than linear HAV4 peptide. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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