The 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.
Keywords: ATP-binding cassette transporters, blood-brain barrier, blood-cerebrospinal fluid barrier, drug delivery, neurovascular unit, solute
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