Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery

Annals of the New York Academy of Sciences
Sophie DithmerLars Winkler

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 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, ...Continue Reading

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Citations

May 9, 2018·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Richard F KeepGuohua Xi
Jun 28, 2018·American Journal of Physiology. Cell Physiology·Wazir AbdullahiPatrick T Ronaldson
Feb 3, 2018·Fluids and Barriers of the CNS·Richard F KeepLester R Drewes
Feb 15, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Lars WinklerReiner F Haseloff
Nov 22, 2018·Frontiers in Physiology·Pablo Torres-VergaraJeffrey Penny
Jan 30, 2019·Fluids and Barriers of the CNS·Chris GreeneMatthew Campbell
Mar 7, 2020·Fluids and Barriers of the CNS·Richard F KeepLester R Drewes
Sep 16, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Patrick T Ronaldson, Thomas P Davis
Jan 6, 2021·Neurochemistry International·Fabien GosseletMaxime Culot
Feb 23, 2021·Advanced Drug Delivery Reviews·Joël BrunnerGerrit Borchard
May 1, 2020·Biochimica Et Biophysica Acta. Biomembranes·Yosuke Hashimoto, Matthew Campbell
Jun 13, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Keisuke TachibanaMasuo Kondoh
May 23, 2020·Drug Discovery Today·Yosuke HashimotoMasuo Kondoh
Aug 14, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Olga Breitkreuz-KorffLars Winkler
Jan 1, 2019·Analytical Chemistry·Hiroaki HatanoYuji Miyahara
Nov 28, 2021·Pharmaceutics·Rory WhelanAndrew J S Knox

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