Effect of Spacers on the Affinity of Tyrosine-Modified Polymers to L-Type Amino Acid Transporter 1

L-type amino acid transporter 1 (LAT1), which takes up neutral amino acids such as tyrosine, is overexpressed on various cancer cells, and many researchers have developed LAT1-targeting drug delivery systems (DDSs) by modifying them with substrates of LAT1. However, none of the previous studies have examined the effects of spacers conjugated with substrates on the interaction between the DDSs and LAT1. Here, we developed polymers with tyrosine-based ligands on the side chains via propyl- or triethylene glycol spacers and compared their targetability to that of LAT1. While both polymers exhibited efficient cellular uptake in cancer cells through endocytosis in an LAT1-selective manner, the polymer with the triethylene glycol spacers exhibited higher cellular uptake efficiency than that with the propyl-spacers. Consistently, in the in vivo study with mice bearing subcutaneous tumors, the polymer with the triethylene glycol spacers showed significantly high tumor accumulation and thereby accomplished tumor-selective delivery of photosensitizers, permitting efficient antitumor activity upon photoirradiation. Our results indicate the importance of the spacer structure in designing DDSs targeting amino acid transporters.