Preclinical evaluation of new α-radionuclide therapy targeting LAT1: 2-[At]astato-α-methyl-L-phenylalanine in tumor-bearing model.

Introduction: Targeted α-radionuclide therapy has attracted attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, we prepared an LAT1-selective α-radionuclide-labeled amino acid analog, 2-[At]astato-α-methyl-L-phenylalanine (2-[At]AAMP), and evaluated its potential as a therapeutic agent.

Methods: 2-[At]AAMP was prepared from the stannyl precursor. Stability of 2-[At]AAMP was evaluated both in vitro and in vivo. In vitro studies using an LAT1-expressing human ovarian cancer cell line, SKOV3, were performed to evaluate cellular uptake and cytotoxicity of 2-[At]AAMP. Biodistribution and therapeutic studies in SKOV3-bearing mice were performed after intravenous injection of 2-[At]AAMP.

Results: 2-[At]AAMP was stable in murine plasma in vitro and excreted intact into urine. Cellular uptake of 2-[At]AAMP was inhibited by treatment with an LAT1-selective inhibitor. After 24 h incubation, 2-[At]AAMP suppressed clonogenic growth at 10 kBq/ml, and induced cell death and DNA double-strand breaks at 25 kBq/ml. When injected into mice, 2-[At]AAMP exhibited peak accumulation in the tumor at 30 min postinjection, and radioactivity levels in the tumor were retained up to 60 min. The majority of the radioactivity was rapidly eliminated from the body into urine in an intact form immediately after injection. 2-[At]AAMP significantly improved the survival of mice (P < 0.05) without serious side effects.

Conclusion: 2-[At]AAMP showed α-radiation-dependent cellular growth inhibition after it was taken up via LAT1. In addition, 2-[At]AAMP had a beneficial effect on survival in vivo. These findings suggest that 2-[At]AAMP would be useful for the treatment of LAT1-positive cancer.

Advances In Knowledge And Implications For Patient Care: This is the first report of an LAT1-targeting radiopharmaceutical for α-radionuclide therapy; this agent would be applicable for the treatment of various types of cancer.