title: Reversible Opening of Intercellular Junctions of Intestinal Epithelial and Brain Endothelial Cells With Tight Junction Modulator Peptides.
abstract: The intercellular junctions restrict the free passage of hydrophilic compounds through the paracellular clefts. Reversible opening of the tight junctions of biological barriers is investigated as one of the ways to increase drug delivery to the systemic circulation or the central nervous system. Six peptides, ADT-6, HAV-6, C-CPE, 7-mer (FDFWITP, PN-78), AT-1002, and PN-159, acting on different integral membrane and linker junctional proteins were tested on Caco-2 intestinal epithelial cell line and a coculture model of the blood-brain barrier. All peptides tested in nontoxic concentrations showed a reversible tight junctions modulating effect and were effective to open the paracellular pathway for the marker molecules fluorescein and albumin. The change in the structure of cell-cell junctions was verified by immunostaining for occludin, claudin-4,-5, ZO-1, β-catenin, and E-cadherin. Expression levels of occludin and claudins were measured in both models. We could demonstrate a selectivity of C-CPE, ADT-6, and HAV-6 peptides for epithelial cells and 7-mer and AT-1002 peptides for brain endothelial cells. PN-159 was the most effective modulator of junctional permeability in both models possibly acting via claudin-1 and -5. Our results indicate that these peptides can be effectively and selectively used as potential pharmaceutical excipients to improve drug delivery across biological barriers.
authors: Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary; Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Hungary.
authors: Alexandra
authors: A
authors: Bocsik
authors: Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary.
authors: Fruzsina R
authors: FR
authors: Walter
authors: Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary.
authors: Andrea
authors: A
authors: Gyebrovszki
authors: Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary.
authors: Lívia
authors: L
authors: Fülöp
authors: Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin-Buch, Germany.
authors: Ingolf
authors: I
authors: Blasig
authors: Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin-Buch, Germany.
authors: Sebastian
authors: S
authors: Dabrowski
authors: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary.
authors: Ferenc
authors: F
authors: Ötvös
authors: Department of Biotechnology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
authors: András
authors: A
authors: Tóth
authors: Department of Biotechnology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
authors: Gábor
authors: G
authors: Rákhely
authors: Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary.
authors: Szilvia
authors: S
authors: Veszelka
authors: Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Hungary.
authors: Monika
authors: M
authors: Vastag
authors: Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Hungary.
authors: Piroska
authors: P
authors: Szabó-Révész
authors: Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary. Electronic address: deli.maria@brc.mta.hu.
authors: Mária A
authors: MA
authors: Deli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism
chemical_list: D010446:Peptide Fragments
keywords: Caco-2 cell line; TJ modulator; blood-brain barrier; brain endothelial cells; intestinal barrier; peptides; permeability enhancer; tight junctions