Preclinical Evaluation of Radiation-Induced Toxicity in Targeted Alpha Therapy Using [211At] NaAt in Mice: A Revisit
Preclinical Evaluation of Radiation-Induced Toxicity in Targeted Alpha Therapy Using [211At] NaAt in Mice: A Revisit
复制标题
DOI：
10.1016/j.tranon.2020.100757
复制
发表时间：
2020-04-01
影响因子：
5
通讯作者：
Hatazawa, Jun
中科院分区：
文献类型：
--
作者：
Liu, Yuwei;Watabe, Tadashi;Hatazawa, Jun
我们最近报道了At-211-NaAt在分化型甲状腺癌异种移植模型中的剂量依赖性治疗作用。在本研究中，我们使用详细的血液学，生物化学和组织学分析评估的辐射诱导的毒性的At-211-NaAt。测定了12只正常ICR小鼠体内At-211-NaAt的生物分布，计算了各主要脏器的吸收剂量。各组ICR小鼠（n = 60）注射0.1 MBq或1 MBq At-211-NaAt，使用生理盐水作为对照组（n = 30）。随访60 d，观察体重和摄食量。分别于注射后3、7、15、29、60 d检测血细胞计数和血清生化指标。用苏木精和伊红染色对主要器官进行组织学分析。生物分布研究显示，甲状腺、胃、膀胱、心脏、肺、脾、肾和睾丸中的吸收剂量较高。0.1 MBq组无异常。1 MBq组显示体重和摄食量降低。组织学分析显示甲状腺萎缩和纤维化，在第29天在一只小鼠的睾丸中发现了短暂的精子生成不足。血液学毒性为轻度和一过性。总胆固醇、白蛋白和总蛋白升高，无恢复迹象，认为是甲状腺功能减退症引起的。高剂量At-211-NaAt给药在白色血细胞和睾丸中显示出一过性毒性，而没有严重的血液学或肾脏毒性，表明其作为分化型甲状腺癌靶向α治疗在1 MBq组中具有可耐受的安全性。
We recently reported the dose-dependent therapeutic effect of At-211-NaAt in differentiated thyroid cancer xenograft models. In the present study, we evaluated the radiation-induced toxicity of At-211-NaAt using detailed hematological, biochemical, and histological analyses. Biodistribution of At-211-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 At-211-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 At-211-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.