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

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 l...

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Bibliographic Details
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
Subjects:
adherens junction
Animals
BBB
BBB modulation
blood-brain barrier
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - metabolism
Brain - drug effects
Brain - metabolism
brain delivery
cadherin peptides
Dipeptides - administration & dosage
Dipeptides - metabolism
Dogs
Drug Delivery Systems - methods
HAV peptide
Humans
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred BALB C
paracellular pathway
Peptides, Cyclic - administration & dosage
Peptides, Cyclic - metabolism
Permeability - drug effects
Rats
Rats, Sprague-Dawley
tight junction
Valine - administration & dosage
Valine - metabolism
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Summary: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 (t1/2 = 12.95 h) has better plasma stability compared with linear HAV4 (t1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2-4 h) compared with HAV4 (
ISSN:0022-3549
1520-6017
DOI:10.1016/S0022-3549(15)00188-4