L-Type Amino Acid Transporter 1 Enables the Efficient Brain Delivery of Small-Sized Prodrug across the Blood-Brain Barrier and into Human and Mouse Brain Parenchymal Cells.

Membrane transporters have long been utilized to improve the oral, hepatic, and renal (re)absorption. In the brain, however, the transporter-mediated drug delivery has not yet been fully achieved due to the complexity of the blood-brain barrier (BBB). Because L-type amino acid transporter 1 (LAT1) is a good candidate to improve the brain delivery, we developed here four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. As a result, all the prodrugs were able to cross the BBB and localize into the brain cells. The brain uptake of salicylic acid (SA) was improved five times, not only across the mouse BBB but also into the cultured mouse and human brain cells. The naproxen prodrug was also transported efficiently into the mouse brain achieving less peripheral exposure, but the brain release of naproxen from the prodrug was not improved. Contrarily, the high plasma protein binding of the flurbiprofen prodrug and the premature bioconversion of the ibuprofen prodrug in the mouse blood hindered the efficient brain delivery. Thus, the structure of the parent drug affects the successful brain delivery of the LAT1-utilizing prodrugs, and the small-sized LAT1-utilizing prodrug of SA constituted a successful model to specifically deliver its parent drug across the mouse BBB and into the cultured mouse and human brain cells.