Transporters at CNS barrier sites: obstacles or opportunities for drug delivery?

Abstract

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.

Figure 1

Cross section of brain capillary endothelial cell. Factors secreted by astrocytes and pericytes, as well as neuronal input help maintain tight junction integrity and function, allowing for limited paracellular permeability of substances into the CNS.

Figure 2

Methods of xenobiotic transport across the blood-barrier

Figure 3

Transport mechanisms expressed in cells comprising the neurovascular unit. A multitude of transporters are expressed on capillary endothelial cells, astrocytes, microglia, and neurons. Transporter systems aid in transport of nutrients, peptides, and ions into the brain parenchyma and as well as efflux of waste and potentially neurotoxic substance out of the brain. Arrows indicate the proposed direction of substrate transport.

Figure 4

Transporter systems expressed on at the BCSF barrier in choroid plexus epithelial cells.