Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery

Abstract

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.

Retinoic acid and hydrocortisone strengthen the barrier function of human RPMI 2650 cells, a model for nasal epithelial permeability

“…In polarized epithelia, tight and adherens junctions can be detected at the apical region of the intercellular cleft and appear as a zipper-like seal between adjacent cells. Intercellular junctions are involved in the control of epithelial paracellular permeability (Deli 2009). They also promote cell-to-cell communication and transfer signals that mediate contact inhibition of cell growth, increase resistance to apoptosis, and regulate cell shape and polarity (Bauer et al 2011).…”

“…The paracellular permeability, one of the most important determinants of drug transport, of various epithelial tissues and barriers differs greatly (Deli 2009). Transepithelial resistance, measuring paracellular ion flux and reflecting the tightness of the intercellular junctional complex, is low in the nasal mucosa, which is considered as a leaky epithelial tissue.…”

“…Transepithelial resistance, measuring paracellular ion flux and reflecting the tightness of the intercellular junctional complex, is low in the nasal mucosa, which is considered as a leaky epithelial tissue. The tight junctions in the epithelium of the small intestine, the stomach and the colon are of intermediate tightness, while endothelial cells of brain capillaries and skin epithelial cells form very tight paracellular barriers (Deli 2009). …”

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

“…Therefore, our present results are consistent with the previous report. In npg addition, calcium depletion by a chelating agent (EDTA) was also reported to increase paracellular permeability [21] , and the P eff -value of FTA was increased as the concentration of EDTA was increased, further illustrating that the absorption of FTA involved paracellular transport. In the Caco-2 cell model in vitro, the P app -value of FTA was enhanced as the concentrations of VER, CSA, and MK571 were increased, exhibiting a clear concentration-dependent effect.…”

“…Therefore, verapamil (VER), a P-gp inhibitor [15] ; cyclosporine (CSA) and MK571, MRP inhibitors [16] ; mannitol (MAN), a SGLT1 inhibitor [17,18] ; diclofenac sodium (DFS) and indomethacin (INDO), OATP inhibitors [19,20] and sodium caprate and EDTA, paracellular permeability enhancers (PPEs) [21,22] were selected to study the absorption mechanism and the factors that infl uence the intestinal absorption of FTA using an in vitro Caco-2 model and an in situ intestinal perfusion model to elucidate why the oral BA of FTA was low and to identify suitable pharmaceutical methods to improve the BA of FTA.…”