Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?
Lucy Sanchez-Covarrubias, Lauren M. Slosky, Brandon J. Thompson, Thomas P. Davis and Patrick T. RonaldsonAffiliation:
Department of Medical Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ, 85724-5050.
AbstractThe blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.
ATP-binding cassette transporters, blood-brain barrier, blood-cerebrospinal fluid barrier, drug delivery, neurovascular unit, solute carriers, transporters.
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