Characteristics of compounds that cross the blood-brain barrier

Abstract

Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.

Figure 1

A generic brain barrier. Adult mammalian brain barriers reduce uncontrolled leakage by constituting a monolayer of cells characterized by intercellular tight junctions, decreased macropinocytosis, and decreased fenetrae. Variations on this theme are seen at the vascular brain barrier, blood-CSF barrier, and the specialty CNS barriers such as the blood-retinal barrier. Most brain barriers have a combination of the other features shown. Pores are saturable transporters that can be energy dependent (as exemplified by P-glycoprotein) or energy independent (GLUT-1), located at the luminal or abluminal membrane, and transport bidirectionally or unidirectionally into or out of the cytoplasm. Saturable transport can also be vesicular based and brain barriers likely have many types of vesicular systems (for example, receptor-mediated transcytosis, clathrin-dependent transport, podocytosis, and caveolae). Scaffolding (for example, actin) is likely highly dynamic and involved in tight junction function and vesicular trafficking. Barrier cells contain receptors (binding sites coupled to intracellular machinery) as well as transporters (binding sites coupled to machinery involved in translocation of the ligand). Brain barriers are enzymatically active and this activity can act as another layer of barrier, and they can secrete substances such as cytokines, nitric oxide, and prostaglandins from either their CNS or peripheral side.