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

概要

〔目的(Purpose)〕
Radioactive iodine (RAI) therapy is used for the treatment of patients with differentiated thyroid cancer. However, a percentage of patients show insufficient therapeutic effect or suffer from recurrence or metastases and become RAI-refractory during follow-up. For these patients, a more effective treatment is needed and 211 At, an alpha-emitter which has similar chemical properties to iodine and is used in targeted alpha therapy, is thought to be ideal. We recently reported the dose-dependent therapeutic effect of 2IIAt-NaAt in differentiated thyroid cancer xenograft models. However, radiation-induced toxicity has not been thoroughly evaluated using the 21 At-NaAt solution with ascorbic acid. In the present study, we aimed to evaluate the radiation-induced toxicity of different doses of2,1 A t-Na At solution at different time points to estimate the time-dependent toxicity.

〔方法ならびに成績(Methods/Results)〕
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.

〔総括(Conclusion)〕
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 IMBq group.