Title:Strategies that Target Tight Junctions for Enhanced Drug Delivery
Volume: 22
Issue: 35
Author(s): Lorenza González-Mariscal, Yanahi Posadas, Jael Miranda, Perla Yaceli Uc, José Mario Ortega-Olvera and Sandra Hernández
Affiliation:
Keywords:
Paracellular drug delivery, tight junctions, adherent junctions, blood-brain barrier, blood-tumor barrier, absorption enhancers.
Abstract: Ions and molecules move across epithelial barriers by two pathways, the transcellular
and the paracellular. The former is taken by lipophilic compounds, or by ions and
molecules that move across the plasma membrane through pumps, carriers or exchangers.
The second route is regulated by the tight junction (TJ) that through paracellular channels,
allows the transport of ions across epithelial barriers. Since, a wide variety of bioactive
molecules like peptides, proteins and oligonucleotides cannot use the transcellular route, due
to their hydrophilic nature, interest has arisen in devising procedures to open the TJ in a
reversible manner for paracellular drug delivery. Here, we describe how different strategies
have been devised to enhance the paracellular intestinal absorption of drugs; to open the
blood-brain barrier (BBB) to allow the penetration of drugs for the treatment of disorders
and tumors of the central nervous system; or to deliver antigens into the subjacent mucosa
associated lymphoid tissues, for the development of mucosal vaccines. The strategies described,
include the use of peptides, antibodies and miRNAs that target proteins of the apical junctional complex,
as well as toxins derived from microorganisms that open the TJ by inducing the contraction of the cortical actomyosin
ring. Also, we describe how paracellular absorption, is enhanced by drugs that extract cholesterol from
the plasma membrane, surfactants, fatty acids, oligosaccharides, cationic polymers, nitric oxide donors and calcium
chelators. Likewise, we explain how the BBB has been opened by employing tumor necrosis factor-α,
bradykinin, short chain alkylglycerols, hyperosmotic mannitol and focused ultrasound.