Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted α-Therapy of Thyroid Cancer
Enhancement of 211At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted α-Therapy of Thyroid Cancer
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DOI：
10.2967/jnumed.118.222638
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发表时间：
2019-09-01
影响因子：
9.3
通讯作者：
Hatazawa, Jun
中科院分区：
文献类型：
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作者：
Watabe, Tadashi;Kaneda-Nakashima, Kazuko;Hatazawa, Jun
AT-211是一种α发射体，具有与碘相似的化学性质，用于靶向α治疗。在本研究中，我们加入抗坏血酸（AA）的At-211溶液，以提高放射化学纯度的astatide和评估其对分化型甲状腺癌，这是其特征在于表达钠/碘同向转运体（NIS）的疗效。方法：制备At-211粗溶液（AA（-））和经AA处理的At-211溶液（AA（1））。在正常雄性Wistar大鼠（n = 6）中比较2种溶液的甲状腺摄取。在AA（1）和AA（-）条件下分析K1-NIS细胞中的细胞摄取。将AA（1）以3种剂量注射到K1-NIS异种移植小鼠中：1 MBq（n = 6）、0.4 MBq（n = 6）和0.1 MBq（n = 6），并将溶剂注射到对照小鼠中（n = 6）。比较4组治疗效果。结果：与AA（-）相比，AA（1）注射大鼠甲状腺的摄取显著增强。细胞摄取分析显示，与AA（-）条件相比，AA（1）条件下K1-NIS细胞对At-211的摄取显著增加。在小鼠异种移植物模型中，K1-NIS肿瘤在给药后3和24小时显示At-211的显著蓄积（分别为22.5 +/- 10.4和12.9 +/-6.8%注射剂量）。At-211给药后，肿瘤生长立即受到抑制，呈剂量依赖性。在生存分析中，At-211组（0.1、0.4和1 MBq）的生存率显著优于对照组。结论：分化型甲状腺癌细胞和正常甲状腺细胞对At-211的摄取均增强。该方法还显示出对K1-NIS异种移植物的剂量依赖性功效，表明其对靶向α治疗的潜在适用性。
At-211 is an alpha-emitter that has similar chemical properties to iodine and is used in targeted alpha-therapy. In the present study, we added ascorbic acid (AA) to At-211 solution to increase the radiochemical purity of astatide and evaluated its efficacy against differentiated thyroid cancer, which is characterized by the expression of sodium/iodide symporter (NIS). Methods: Crude At-211 solution (AA(-)) and At-211 solution treated with AA (AA(1)) were prepared. Uptake by the thyroid was compared between the 2 solutions in normal male Wistar rats (n = 6). Cellular uptake in K1-NIS cells was analyzed under the AA(1) and AA(-) conditions. AA(1) was injected at 3 doses into K1-NIS xenograft mice: 1 MBq (n = 6), 0.4 MBq (n = 6), and 0.1 MBq (n = 6), and vehicle was injected into control mice (n = 6). The treatment effects were compared among the 4 groups. Results: Uptake by the thyroid was significantly enhanced in rats injected with the AA(1) as compared with those injected with AA(-). Cellular uptake analysis showed significantly increased uptake of At-211 by the K1-NIS cells under the AA(1) condition as compared with the AA(-) condition. In the mouse xenograft model, the K1-NIS tumors showed significant accumulation of At-211 at 3 and 24 h after administration (22.5 +/- 10.4 and 12.9 +/- 6.8 percentage injected dose, respectively). Tumor growth was immediately inhibited in a dose-dependent manner after administration of At-211. In the survival analysis, the At-211 groups (0.1, 0.4, and 1 MBq) showed significantly better survival than the control group. Conclusion: Uptake of At-211 was enhanced in differentiated thyroid cancer cells as well as the normal thyroid using At-211 solution treated with AA. The method also showed dose-dependent efficacy against the K1-NIS xenografts, suggesting its potential applicability to targeted alpha-therapy.