Targeted alpha therapy using astatine (211At)-labeled phenylalanine: A preclinical study in glioma bearing mice
Tadashi Watabe, Kazuko Kaneda‐Nakashima, Yoshifumi Shirakami, Yuwei Liu, Kazuhiro Ooe, Takahiro Teramoto, Atsushi Toyoshima, Eku Shimosegawa, T. Nakano, Yoshikatsu Kanai, Atsushi Shinohara, Jun Hatazawa
Abstract
// Tadashi Watabe 1 , 2 , Kazuko Kaneda-Nakashima 2 , 3 , Yoshifumi Shirakami 2 , Yuwei Liu 1 , Kazuhiro Ooe 1 , 2 , Takahiro Teramoto 2 , Atsushi Toyoshima 2 , Eku Shimosegawa 2 , 4 , Takashi Nakano 2 , 5 , Yoshikatsu Kanai 6 , Atsushi Shinohara 2 , 7 and Jun Hatazawa 2 , 5 1 Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, Suita, Japan 2 Institute for Radiation Sciences, Osaka University, Suita, Japan 3 Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, Toyonaka, Japan 4 Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Suita, Japan 5 Research Center for Nuclear Physics, Osaka University, Ibaraki, Japan 6 Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Japan 7 Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Japan Correspondence to: Tadashi Watabe, email: [email protected] Keywords: alpha therapy; astatine; glioma; LAT1; phenylalanine Received: January 28, 2020     Accepted: March 14, 2020     Published: April 14, 2020 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 ( 211 At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211 At-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- 211 At-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 211 At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211 At-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.