L-Type amino acid transporter 1 (LAT1) is a transporter protein that is essential for the transport of large neutral amino acids such as L-phenylalanine, L-leucine and L-isoleucine from extracellular fluids into the cells. Additionally, it transports amino acid-containing drugs such as gabapentin, L-DOPA and baclofen across the blood-brain barrier (BBB). In normal cell membranes LAT1 is expressed mainly in blood-brain and blood-placenta barriers. Much of its appeal as a drug carrier is due to its relative high abundance at the BBB versus other tissues (&gt;100 × BBB selective). Besides having an important role in brain delivery, LAT1 is significantly up-regulated in several human cancer types including e.g., brain and breast cancers. This up-regulation may also be exploited in carrier-mediated drug transport into various tumors. For example, the anticancer phenylalanine mustard, melphalan, which was approved by the FDA in 1984, is to some extent transported and accumulated in cancer cells by LAT1. Prodrug approach targeting nutrient transporters such as LAT1 is an attractive strategy for improving the brain and/or cancer cell accumulation of drugs. In our laboratory, several various amino acid prodrugs of e.g. ketoprofen, valproic acid and temozolomide have been designed and synthesized, and their ability to utilize LAT1 have been evaluated with various in vitro, in situ and in vivo experiments. Of several amino acid prodrugs studied, especially L-tyrosine and L-lysine derivatives were observed to efficiently bind to LAT1 in stably expressing hLAT1 cell line (HEK-hLAT1) and in in situ rat brain perfusion experiments. Prodrugs also showed concentration-dependent and saturable uptake further suggesting that their uptake was carrier-mediated. In addition, the ability of prodrugs to deliver active drugs into the brain intracellular fluid was demonstrated for one prodrug by combining various in vivo and in vitro experiments. Our experiments have also resulted in ligand-based 3D-pharmacophore and 3D-QSAR models of the common structural features responsible for efficient LAT1 binding. Together, these results indicate that LAT1-targeted prodrugs may offer a potential approach to deliver small-molecular weight drugs into CNS and cancer cells even though one of the L-lysine prodrugs was associated with adverse neuropathological effects after its chronic administration warranting further investigations.

LAT1-targeted prodrugs in brain and cancer drug delivery

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ACS Fall 2022

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