Reversible Opening of Intercellular Junctions of Intestinal Epithelial and Brain Endothelial Cells with Tight Junction Modulator Peptides

Alexandra Bocsik, Fruzsina R. Walter, Andrea Gyebrovszki, L. Fülöp, Ingolf Blasig, Sebastian Dabrowski, F. Ötvös, András Tóth, G. Rákhely, S. Veszelka, Monika Vastag, P. Szabó-Révész, M. Deli

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)754-765
Number of pages12
JournalJournal of Pharmaceutical Sciences
Volume105
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

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Keywords

  • blood-brain barrier
  • brain endothelial cells
  • Caco-2 cell line
  • intestinal barrier
  • peptides
  • permeability enhancer
  • tight junctions
  • TJ modulator

ASJC Scopus subject areas

  • Pharmaceutical Science

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