Preclinical Evaluation of Radiation-Induced Toxicity in Targeted Alpha Therapy Using [211At] NaAt in Mice: A Revisit

Yuwei Liu; Tadashi Watabe; Kazuko Kaneda-Nakashima; Kazuhiro Ooe; Yoshifumi Shirakami; Atsushi Toyoshima; Eku Shimosegawa; Takashi Nakano; Atsushi Shinohara; Jun Hatazawa

doi:10.1016/j.tranon.2020.100757

Preclinical Evaluation of Radiation-Induced Toxicity in Targeted Alpha Therapy Using [²¹¹At] NaAt in Mice: A Revisit

Transl Oncol. 2020 Apr;13(4):100757. doi: 10.1016/j.tranon.2020.100757. Epub 2020 Mar 25.

Authors

Affiliations

¹ Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Electronic address: liu@tracer.med.osaka-u.ac.jp.
² Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan. Electronic address: watabe@tracer.med.osaka-u.ac.jp.
³ Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan; Core for Medicine and Science Collaborative Research and Education, Project Research Center for Fundamental Sciences, Osaka University Graduate School of Science, Toyonaka, Osaka, Japan.
⁴ Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan.
⁵ Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan.
⁶ Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan; Department of Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
⁷ Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan; Research Center for Nuclear Physics, Osaka University, Ibaraki, Osaka, Japan.
⁸ Institute for Radiation Sciences, Osaka University, Toyonaka, Osaka, Japan; Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.

Abstract

We recently reported the dose-dependent therapeutic effect of ²¹¹At-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of ²¹¹At-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of ²¹¹At-NaAt was measured in normal ICR mice (n = 12), absorbed doses in the major organs were calculated. Groups of ICR mice (n = 60) were injected with 0.1 MBq or 1 MBq of ²¹¹At-NaAt, using saline as the control group (n = 30). Body weight and food intake were followed up for 60 days. Blood cell counts and serum level of biochemical parameters were measured 3, 7, 15, 29, 60 days after injection. Histological analyses of the major organs with hematoxylin and eosin staining were performed. Biodistribution study revealed a high-absorbed dose in the thyroid gland, stomach, bladder, heart, lungs, spleen, kidneys, and testis. The 0.1 MBq group showed no abnormalities. The 1 MBq group showed decreased body weight and food intake. Histological analysis showed atrophy and fibrosis in the thyroid gland, a transient hypospermatogenesis in the testis on day 29 was found in one mouse. Hematological toxicity was mild and transient. The total cholesterol, albumin, and total protein increased with no signs of recovery, which was considered to be caused by hypothyroidism. High-dose administration of ²¹¹At-NaAt showed transient toxicity in the white blood cells and testis without severe hematological or renal toxicity, suggesting its tolerable safety as targeted alpha-therapy for differentiated thyroid cancer in the 1 MBq group.