Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9022175 | International Congress Series | 2005 | 12 Pages |
Abstract
Drug delivery to brain can be improved through the design of novel therapeutic agents that are rapidly and selectively shuttled into the nervous system across the blood-brain barrier (BBB) by the facilitated influx transporters of brain capillaries. Messenger RNA analysis has demonstrated high expression of >20 influx transporters at the BBB, including carriers for glucose (GLUT1), monocarboxylic acids (MCT1), large neutral amino acids (LAT1), cationic amino acids (CAT1), and nucleosides (ENT 1-2, CNT1-2) and choline. Expression of these transporters at the BBB is enriched 10-100 fold relative to whole brain tissue. Several polar therapeutic drugs gain entry to brain via carrier-mediated transport, including l-DOPA, α-methyl-DOPA, gabapentin, and melphalan. However, transport affinity for these agents is low and brain delivery is limited. Three-D structure-activity studies demonstrate that brain delivery can be improved >10 fold by incorporating substrate modifications that enhance carrier binding and transport. Specific examples are given in this paper for BBB LAT1 transport of two anticancer alkylating drugs, l-metasarcolysin and d,l-NAM. In summary, a broad array of highly expressed carrier-mediated transport systems is available at the BBB that can be used to enhance brain delivery for selected agents.
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Authors
Quentin R. Smith,