Polymeric ligands comprising sulfur-containing amino acids for targeting tumor-associated amino acid transporters

• Published in: Biomaterials Vol. 293; p. 121987
• Main Authors: Guo, Haochen, Xu, Wen, Nomoto, Takahiro, Kanamori, Kaito, Voon, Yan Ming, Honda, Yuto, Yamada, Naoki, Takemoto, Hiroyasu, Matsui, Makoto, Nishiyama, Nobuhiro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2023
• Subjects: Amino Acid Transport Systems; amino acid transporters; Amino Acids; biocompatible materials; cysteine; drugs; Humans; Large Neutral Amino Acid-Transporter 1 - metabolism; LAT1; ligands; Methionine; Methionine - metabolism; Multivalent effect; Neoplasms - metabolism; phenylalanine; photochemistry; Photodynamic therapy; photoirradiation; Polymer; polymers; Polymers - metabolism; Racemethionine; Sulfur - metabolism; therapeutics; Tumor targeting; LAT1; Polymer; Photodynamic therapy; Tumor targeting; Multivalent effect; Methionine
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2022.121987

Various cancer cells overexpress L-type amino acid transporter 1 (LAT1) to take up a large number of neutral amino acids such as phenylalanine and methionine, and LAT1 transporter should be a promising target for cancer diagnosis and therapy. However, only a few studies reported drug delivery systems targeting LAT1 probably due to limited knowledge about the interaction between LAT1 and its substrate. Here, we developed polymers having methionine (Met)- or cysteine (Cys)-like structures on their side chains to examine their affinity with LAT1. While both the Met- and Cys-modified polymers exhibited efficient cellular uptake selectively in cancer cells, the Met-modified polymers exhibited higher cellular uptake efficiency in an LAT1-selective manner than the Cys-modified polymers. In the in vivo study, the intraperitoneally injected Met-modified polymers showed appreciable tumor-selective accumulation in the peritoneal dissemination model, and importantly, Met-modified polymers conjugated with photosensitizers exhibited significant therapeutic effects upon photoirradiation with reduced photochemical damage to normal organs. Our results may provide important knowledge about the polymer-LAT1 interaction, and the Met-modified polymers should offer a new concept for designing LAT1-targeting drug delivery systems.