Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 8: Blood-Brain Barrier: Considerations in Drug Development and Delivery

David S. Miller

Brian T. Hawkins

Research Triangle Park, Laboratory of Pharmacology, NIH/NIEHS, North Carolina

The brain capillary endothelium, which comprises the blood-brain barrier, provides an exceptionally effective barrier to the entry of foreign chemicals into the central nervous system (CNS). As such, it limits pharmacotherapy of major CNS diseases, which include neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS. Two elements of the endothelium are largely responsible for its barrier properties. First, tight junctions between endothelial cells present a physical barrier. Second, endothelial cells themselves express high levels of adenosine triphosphate (ATP)-driven drug efflux transporters, which present a selective/enzymatic barrier. Together, the physical and enzymatic barriers effectively limit blood to CNS delivery of both small-molecule and macromolecule drugs. Developing strategies to circumvent these barriers is a major challenge for both medicinal chemists and pharmacologists.

For a drug to be effective, it must access its site of action and be present for a long enough time and at a high enough concentration to have a therapeutic effect. In this regard, drug delivery to the brain is a serious and long-standing problem in pharmacotherapy of central nervous system (CNS) disorders. On the one hand, invasive approaches that involve the direct introduction of drugs into ...