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Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery
Author(s) -
Dithmer Sophie,
Staat Christian,
Müller Carolin,
Ku MinChi,
Pohlmann Andreas,
Niendorf Thoralf,
Gehne Nora,
FallierBecker Petra,
Kittel Ágnes,
Walter Fruzsina R.,
Veszelka Szilvia,
Deli Maria A.,
Blasig Rosel,
Haseloff Reiner F.,
Blasig Ingolf E.,
Winkler Lars
Publication year - 2017
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.13359
Subject(s) - peptidomimetic , blood–brain barrier , tight junction , claudin , chemistry , biophysics , drug delivery , peptide , endothelial stem cell , microbiology and biotechnology , biochemistry , in vitro , biology , organic chemistry , neuroscience , central nervous system
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 μmol/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 β‐sheets flanked by α‐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.