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Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery

Item Type:Article
Title:Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery
Creators Name:Dithmer, S. and Staat, C. and Müller, C. and Ku, M.C. and Pohlmann, A. and Niendorf, T. and Gehne, N. and Fallier-Becker, P. and Kittel, Á. and Walter, F.R. and Veszelka, S. and Deli, M.A. and Blasig, R. and Haseloff, R.F. and Blasig, I.E. and Winkler, L.
Abstract:The blood-brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (≤40 kDa) and reversibly (12-48 h) increased the permeability of brain endothelial and claudin-5-transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed from cell-cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 {mu}mol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd-diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an association model between {beta}-sheets flanked by {alpha}-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.
Keywords:Tissue Barrier, Blood-Brain Barrier, Cell-Cell Contact, Tight Junction, Claudin Protein Family, Peptide, Animals, Mice, Rats
Source:Annals of the New York Academy of Sciences
Publisher:New York Academy of Sciences
Page Range:169-184
Date:June 2017
Official Publication:https://doi.org/10.1111/nyas.13359
PubMed:View item in PubMed

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