Abstract
IntroductionTargeted 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-[211At]astato-α-methyl-L-phenylalanine (2-[211At]AAMP), and evaluated its potential as a therapeutic agent. Methods2-[211At]AAMP was prepared from the stannyl precursor. Stability of 2-[211At]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-[211At]AAMP. Biodistribution and therapeutic studies in SKOV3-bearing mice were performed after intravenous injection of 2-[211At]AAMP. Results2-[211At]AAMP was stable in murine plasma in vitro and excreted intact into urine. Cellular uptake of 2-[211At]AAMP was inhibited by treatment with an LAT1-selective inhibitor. After 24 h incubation, 2-[211At]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-[211At]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-[211At]AAMP significantly improved the survival of mice (P < 0.05) without serious side effects. Conclusion2-[211At]AAMP showed α-radiation-dependent cellular growth inhibition after it was taken up via LAT1. In addition, 2-[211At]AAMP had a beneficial effect on survival in vivo. These findings suggest that 2-[211At]AAMP would be useful for the treatment of LAT1-positive cancer. Advances in knowledge and implications for patient careThis 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.
Highlights
Targeted radionuclides therapy with α-emitters has drawn global attention
A reversed-phase HPLC (RP-HPLC) analysis was performed with a C18 column (Capcell Pak C18 AQ, 4.6 × 250 mm; Shiseido Co., Tokyo, Japan) at a flow rate of 1 ml/min eluted with a linear gradient of 0.1% aqueous trifluoroacetic acid (TFA) and acetonitrile with 0.1%TFA from 90:10 to 0:100 for 30 min
The first-step reaction proceeded in high radiochemical yield (>95%, Fig. S1), total radiochemical yield of [211At]-2-AAMP determined by Thinlayer chromatography (TLC) was 20.9±3.3%
Summary
Targeted radionuclides therapy with α-emitters has drawn global attention. Linear energy transfer (LET) of α-particle is approximately 80 keV/μm, and α-radiation is considered to be high-LET radiation [1, 2]. Path-length of α-particle in water is short (50 ~ 100 μm) [1, 2]. These characteristics are beneficial in eliminating tumors and reducing damages in normal tissues surrounding the tumor. More than ten clinical studies have shown the significant improvements of survival after treatment with α-emitter labeled carriers targeting specific molecules for cancer, such as CD33, prostate specific membrane antigen (PSMA), and somatostatin receptor (SSTR) [5,6,7]. The application of these radiopharmaceuticals is limited to certain types of cancers expressing these target molecules. Radiopharmaceuticals targeting molecules that express on various types of cancers would enable the wider use of targeted α-therapy
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