Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery.
The epithelial and endothelial barriers of the human body are major obstacles for drug delivery to the systemic circulation and to organs with unique environment and homeostasis, like the central nervous system. Several transport routes exist in these barriers, which potentially can be exploited for enhancing drug permeability. Beside the transcellular pathways via transporters, adsorptive and receptor-mediated transcytosis, the paracellular flux for cells and molecules is very limited. While lipophilic molecules can diffuse across the cellular plasma membranes, the junctional complexes restrict or completely block the free passage of hydrophilic molecules through the paracellular clefts. Absorption or permeability enhancers developed in the last 40 years for modifying intercellular junctions and paracellular permeability have unspecific mode of action and the effective and toxic doses are very close. Recent advances in barrier research led to the discovery of an increasing number of integral membrane, adaptor, regulator and signalling proteins in tight and adherens junctions. New tight junction modulators are under development, which can directly target tight or adherens junction proteins, the signalling pathways regulating junctional function, or tight junction associated lipid raft microdomains. Modulators acting directly on tight junctions include peptides derived from zonula occludens toxin, or Clostridium perfringens enterotoxin, peptides selected by phage display that bind to integral membrane tight junction proteins, and lipid modulators. They can reversibly increase paracellular transport and drug delivery with less toxicity than previous absorption enhancers, and have a potential to be used as pharmaceutical excipients to improve drug delivery across epithelial barriers and the blood-brain barrier.
Deli
Mária A
MA
Institute of Biophysics, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62., H-6726 Szeged, Hungary. deli@brc.hu
D022005:Adherens Junctions / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D002772:Cholera Toxin / Q000502:physiology; D062445:Claudin-1; D016503:Drug Delivery Systems; D006242:Haptoglobins; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D021962:Membrane Microdomains / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects; D062793:Occludin; D011498:Protein Precursors; D015398:Signal Transduction / Q000502:physiology; D019108:Tight Junctions / Q000187:drug effects*
C568108:CLDN1 protein, human; D002614:Chelating Agents; D062445:Claudin-1; D006242:Haptoglobins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D011498:Protein Precursors; C408043:zonulin; D002772:Cholera Toxin