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.
Highlights
The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system (CNS)
This suggests that the BBB itself could be used as the source of CNS 'drugs'
Transmembrane diffusion, harnessing of transporters, adsorptive endocytosis, and extracellular pathways are some of the mechanisms being exploited for drug delivery
Summary
The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system (CNS). Drug delivery tends to focus on the vascular BBB, the blood-CSF barrier presents special opportunities [2] At both sites, the BBB is formed by a monolayer of cells that are cemented together by tight junctions and have other mechanisms that control or retard leakage of plasma into the CNS (Figure 1). It is known that these substances are all substrates for Pglycoprotein, a major brain-to-blood, or efflux, pump located at the BBB that prevents or greatly retards a large number of small, lipid soluble molecules from entering the CNS [12,13]. Luminal receptors that induce brain endothelial cells to secrete into the CNS substances such as prostaglandins, cytokines, and nitric oxide are readily targetable This suggests that the BBB itself could be used as the source of CNS 'drugs'. How epinephrine invokes this re-induction of activity is unclear, but it may be a useful strategy for delivery of enzyme to the CNS
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