Enhancement of²¹¹At Uptake via the Sodium Iodide Symporter by the Addition of Ascorbic Acid in Targeted α-Therapy of Thyroid Cancer

Abstract

211At is an α-emitter that has similar chemical properties to iodine and is used in targeted α-therapy. In the present study, we added ascorbic acid (AA) to 211At 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 211At solution (AA(−)) and 211At solution treated with AA (AA(+)) 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(+) and AA(−) conditions. AA(+) 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(+) as compared with those injected with AA(−). Cellular uptake analysis showed significantly increased uptake of 211At by the K1-NIS cells under the AA(+) condition as compared with the AA(−) condition. In the mouse xenograft model, the K1-NIS tumors showed significant accumulation of 211At 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 211At. In the survival analysis, the 211At groups (0.1, 0.4, and 1 MBq) showed significantly better survival than the control group. Conclusion: Uptake of 211At was enhanced in differentiated thyroid cancer cells as well as the normal thyroid using 211At solution treated with AA. The method also showed dose-dependent efficacy against the K1-NIS xenografts, suggesting its potential applicability to targeted α-therapy.

Targeted alpha therapy using astatine (211At)-labeled phenylalanine: A preclinical study in glioma bearing mice

“…The estimated absorbed dose in the C6 glioma xenograft was 1.7 ± 0.6 Gy/MBq. In our previous study using 211 At-NaAt, the estimated dose was 9.7 ± 7.0 Gy/MBq in the K1-NIS xenograft, which showed better tumor retention [11]. Regarding the treatment effect, 211 At-NaAt treatment showed tumor Oncotarget 1392 www.oncotarget.com regression followed by the delayed regrowth, whereas 211 At-AtPA treatment showed tumor growth suppression in a dose dependent manner.…”

“…211 At-astatide is thought to be deastatinated during metabolic processes. We have previously reported the specific uptake of astatide in the thyroid gland through the sodium iodide symporter (NIS), in a manner similar to iodide, and identified the thyroid gland as an organ at risk [11]. We subsequently demonstrated that the thyroid uptake of 211 At-astatide, which was deastatinated from 211 At-PA, could be reduced by 80% following the pre-administration of iodine [22].…”

“…Our findings suggest that 211 At-PA could be useful as an alpha therapy specific for system L amino acid transporters expressed on malignant tumors. 211 At was procured from the Research Center for Nuclear Physics at Osaka University and RIKEN via Supply Platform of Short-lived Radioisotopes [11]. 211 At was produced in the 209 Bi (α,2n) 211 At reaction using the AVF Cyclotron.…”

“…In contrast, the alpha emitter astatine ( 211 At) is a halogen element with a relatively short half-life (7.2 hr) and simple decay chain. 211 At can be produced in a commercially available medium-energy cyclotron by alpha beam irradiation of a bismuth target [11]. In addition, 211 At can be combined with small molecule compounds to enable rapid distribution to the target.…”

Dispersal rates of astatine-211 from aqueous solutions and chloroform

“…In addition, we used 100 mL beakers and smaller 1.5 mL microtubes as vessels for 211 At aliquots to examine the vessel-size dependence of the dispersal rate of 211 At. Thin-layer chromatography (TLC), which is often used for chemical analysis of pharmaceuticals 8) and chemical studies 9) of At, was also performed to obtain information on formed chemicals species of 211 At. After bombardment, 211 At was separated from the irradiated Bi target 10) .…”