Dual Action of the PN159/KLAL/MAP Peptide: Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability

Pharmaceutics

Norbert Imre¹  TamásA. Martinek¹  Lívia Fülöp¹  Piroska Szabó-Révész²  Monika Vastag³  Lejla Daruka⁴  Ferenc Ötvös⁵  Lóránd Kiss⁶  Ilona Gróf⁶  MáriaA. Deli⁶  Alexandra Bocsik⁶  Ágnes Kittel⁷  Ottó Zsíros⁸  Csaba Pál⁹ 

[1] Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary;Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Hungary;Division of Pharmacology and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Hungary;Doctoral School in Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary;Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary;Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary;Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary;Plant Biology, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary;Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Hungary;

关键词: absorption enhancer;    antimicrobial peptide;    Caco-2;    claudin;    cell-penetrating peptide (CPP);    drug delivery;    intestinal epithelial cells;    KLAL;    PN159;    tight junction modulator;   

DOI  :  10.3390/pharmaceutics11020073

来源: DOAJ

【 摘 要 】

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood⁻brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects.

【 授权许可】

Unknown