Among several natural products, capsaicin has been studied for its therapeutic properties to treat various chronic diseases. While it has shown promising effects in several disease models, high lipophilicity and strong metabolism limit its therapeutic use to local injections and topical administration. Moreover, high concentrations of capsaicin cause severe adverse effects. Thus, the present study aimed to synthesize a novel phenylalanine-derived prodrug of capsaicin that would utilize L-type amino acid transporter 1 (LAT1) for its delivery. The proposed prodrug strategy aimed to improve capsaicin's therapeutic effects in the brain and pancreas, where LAT1 is expressed. The results showed that the cellular uptake into microglia, astrocytes, and pancreatic β-cells increased up to 250-fold by a LAT1-mediated delivery. In the in vivo pharmacokinetic study, more stable drug delivery into the pancreas and brain was observed in mice. By the prodrug design, the exposure time was prolonged from 30 min to 90 min, and peak concentrations of capsaicin were lowered. The novel prodrug did not affect human plasma coagulation, nor induce hemolysis or reactive oxygen species production in vitro. Yet, it inhibited mice's prostaglandin D2 and E2 productionafter lipopolysaccharide induction. To summarize, utilization of LAT1 increased prodrug delivery simultaneously in both the pancreas and brain, allowing dual-targeting of capsaicin. This is a beneficial strategy when developing treatment against diseases interlinked in the brain and pancreas, namely neurodegenerative diseases and diabetes.
