The L-type amino acid transporter 1 enhances drug delivery to the mouse pancreatic beta cell line (MIN6)

Abstract

L-type amino acid transporter 1 (LAT1) is a membrane transporter responsible for carrying large, neutral L-configured amino acids as well as appropriate (pro)drugs into a cell. It has shown a great potential to improve drug delivery across the blood-brain barrier and to increase cell uptake into several brain and cancer cell types. However, besides the brain, the LAT1-utilizing compounds are also delivered more efficiently into the pancreas in vivo. In this study, we quantified the expression of LAT1 along several other membrane transporters in mouse pancreatic β-cell line (MIN6). Furthermore, we studied the function of LAT1 in MIN6 cells, and its ability to deliver non-steroidal anti-inflammatory drug (NSAID)-derived prodrugs there. The results showed that LAT1 was highly abundant in MIN6 cells, with an even expression on cell pseudoislets. The L-leucine uptake as a probe substrate was efficient, with comparable affinity and capacity to previously studied mouse immortalized microglia (BV2). The NSAID-derived prodrugs utilized LAT1 for their delivery and were uptaken into MIN6 cells 2–300 times more efficiently when compared to their parent drugs. A similar increase in pancreatic delivery was observed also in vivo, where the pancreatic exposure was 2–10 times higher with selected prodrugs, indicating an excellent correlation between in vitro uptake and in vivo pancreatic delivery. Finally, the LAT1-utilizing prodrugs were able to reverse the effects of cytokines on insulin secretion in MIN6 cells, showing that improved delivery via LAT1 can enhance drug effects in the mouse pancreatic β-cell line.