Glutathione transporter as a target for brain drug delivery

Abstract

Inability to achieve therapeutic concentrations of a medication in the brain due to the blood brain barrier (BBB) is the major cause of treatment failure for most brain diseases. The BBB prevents almost 98% of small molecule drugs and almost all large molecule therapeutics from entering the brain. Modifying a drug delivery system with a brain targeting agent has been an effective approach in developing a brain targeting drug delivery system. Most of the brain targeting agents were developed based on a receptor- or carrier-mediated endocytosis process at the BBB. These endocytosis processes are transporting mechanisms for transporting endogenous molecules into the brain. They include those for transporting transferrin, LDL (low density lipoprotein), insulin, etc., with transferrin receptor-mediated endocytosis being the most investigated and successful one for developing a brain targeting agent. The Na⁺-dependent glutathione transporter is present on the luminal side of the capillary endothelial cells of the brain, kidneys, and small intestine while its presence on the luminal side of the capillary endothelial cells of other organs is very minimal. This organ distribution difference enables the brain, kidneys and small intestines to sequester GSH from the blood circulation to meet the need of these organs for GSH, and provide a solid foundation for developing organ selective agents for these organs in general. This review provides an overview of the GSH transporter and the status of GSH transporter-based brain targeting drug delivery systems with the intention of bringing the field to the attention of a medicinal chemist for his/her expertise in organic synthesis, ligand identification and optimization.