Abstract
Phenylalanine derivatives, which target tumors especially through L-type amino acid transporter-1 (LAT1), have elicited considerable attention. In this study, we evaluated the treatment effect of phenylalanine labeled with the alpha emitter astatine (211At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211At-PA uptake analysis that included an evaluation of the uptake inhibition by the system L amino acid transporter inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH significantly inhibited para-211At-PA uptake in C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 (12.6 ± 2.0%) cells compared to baseline, suggesting an uptake contribution by system L amino acid transporters. Subsequently, xenograft and allograft models were prepared by subcutaneously injecting C6 glioma (n = 12) or GL-261 cells (n = 12), respectively. C6 glioma mice received three 211At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211At-PA exhibited a tumor growth suppression effect in C6 glioma models in a dose-dependent manner as well as in GL-261 models. This phenylalanine derivative labeled with astatine may be applicable as an alpha therapy that specifically targets system L amino acid transporters.
Highlights
Targeted alpha therapy has received attention as an effective form of radionuclide treatment, for refractory and/or recurrent malignant tumors such as malignant glioma
We evaluated the selectivity of 211At-para-astato-L-PA (211AtPA) for amino acid transporters focusing on L-type amino acid transporter 1 (LAT1), as well as the treatment effect of this derivative in mouse glioma xenograft and allograft models
In the cellular uptake analysis, the addition of BCH significantly inhibited uptake by C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 cells (12.6 ± 2.0%), suggesting that 211At-PA uptake is predominantly mediated by system L amino acid transporters (Figure 2)
Summary
Targeted alpha therapy has received attention as an effective form of radionuclide treatment, for refractory and/or recurrent malignant tumors such as malignant glioma. Phenylalanine (PA) derivatives such as 18F-fluoro-boronoPA (18F-FBPA) and 4-borono-L-PA (BPA) target tumors and are used mainly in the context of boron neutron capture therapy [5] They were both reported to be substrates of the L-type amino acid transporter 1 (LAT1) and were found to be taken up selectively by tumors, with minimal physiological accumulation in normal organs [5, 6]. The corresponding 131I derivative (131I-IPA) has been studied as a therapeutic agent, and is currently being advanced as a combination therapy with external beam radiation in a PhaseI/II clinical trial [8, 9] These PA-based compounds exhibit characteristics of high tumor to normal brain ratio that would be ideal for a targeted alpha therapeutic strategy
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