Carrier-mediated transport to enhance drug delivery to brain

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.