Ⅰ. HIGHLIGHTS OF THE YEARRIKEN Accel. Prog. Rep. 53

Targeted alpha therapy of thyroid cancer: Evaluation of [211 At]NaAt
treatment in the xenograft model†
T. Watabe,∗2,∗3 K. Kaneda-Nakashima,∗3,∗4 Y. Liu,∗2 Y. Shirakami,∗3 K. Ooe,∗1,∗2 A. Toyoshima,∗1,∗3E. Shimosegawa,∗2 M. Fukuda,∗3,∗5 A. Shinohara,∗3,∗4 and J. Hatazawa∗3,∗5
Radioactive iodine has long been used clinically forpatients with diﬀerentiated thyroid cancer.1) 131 I is usedfor the ablation of thyroid remnants or treatment ofmetastatic thyroid cancer.1) However, some patientswith multiple metastases are refractory to repetitive 131I
treatment, despite the targeted regions showing suﬃcientiodine uptake.2) In such patients, beta-particle therapy
using 131 I is inadequate, and another strategy using amore eﬀective radionuclide targeting the sodium/iodide
symporter (NIS) is required.
211
At is an alpha emitter with chemical properties similar to those of iodine and is used in targeted alpha therapy. In the present study, we added ascorbic acid (AA)to 211 At solution to increase the radiochemical purity ofastatide and evaluated its eﬃcacy against diﬀerentiatedthyroid cancer, which is characterized by the expressionof NIS.
Methods
211
At was procured from the Research Center for Nuclear Physics at Osaka University and RIKEN via theshort-lived RI supply platform. Upon procurement,
211
At was separated and puriﬁed via dry distillation froma bismuth target and ﬁnally collected in distilled water.
Crude 211 At solution (AA(−) solution) and 211 At solution treated with AA (AA(+) solution) were prepared.
Thyroid uptakes were compared between the two solutions in normal male Wistar rats (n = 6). Cellularuptake analysis in K1-NIS cells was performed underthe AA(+) and AA(−) conditions. The AA(+) solution was injected at three doses into K1-NIS xenograft
mice: 1 MBq (n = 6), 0.4 MBq (n = 6), and 0.1 MBq(n = 6). The vehicle was injected into control mice(n = 6). The treatment eﬀects were compared among
the four groups. Planar and SPECT images were acquired using a gamma camera system (E-cam, Siemens)with a low-energy all-purpose collimator.3) The energy
window was set at 79 keV ± 20%, targeting the X-rays
emitted from the daughter nuclide of 211 Po.4)
All the animal experiments were performed in compliance with the guidelines of the Institute of Experimental
Animal Sciences. The protocol was approved by the Animal Care and Use Committee of the Osaka University
Graduate School of Medicine.
Results
Thyroid uptake was signiﬁcantly enhanced in rats injected with the AA(+) solution as compared to those†

∗1
∗2
∗3
∗4
∗5

Condensed from the article in J. Nucl. Med. 60, 1301, (2019)
RIKEN Nishina Center
Graduate School of Medicine, Osaka University
Institute for Radiation Sciences, Osaka University
Graduate School of Science, Osaka University
Research Center for Nuclear Physics, Osaka University

Fig. 1. (A) Planar and SPECT images of the mouse K1-NIS
xenograft model after the injection of the AA(+) solution.
High uptake was observed in the xenografts (arrows). (B)Change in the tumor size and body weight after the administration of AA(+) solutions.

injected with the AA(−) solution. Cellular uptake analysis showed a signiﬁcantly increased uptake of 211 At by
the K1-NIS cells under the AA(+) condition as comparedto the AA(−) condition. In the mouse xenograft model,
the K1-NIS tumors showed a signiﬁcant accumulation of211
At 3 and 24 h post administration (22.5 ± 10.4% ID
and 12.9 ± 6.8% ID, respectively). Tumor growth wasimmediately inhibited in a dose-dependent manner after
the administration of 211 At. In the survival analysis, the211
At groups (0.1, 0.4, and 1 MBq) showed signiﬁcantly
better survival than the control group.
Conclusion
The uptake of 211 At was enhanced in diﬀerentiatedthyroid cancer cells as well as normal thyroid by using
211
At solution treated with AA. The solution also showed
dose-dependent eﬃcacy against the K1-NIS xenografts,
suggesting its potential applicability to targeted alphatherapy.
References

1) T. Higashi et al., Ann. Nucl. Med. 26, 99 (2012).
2) M. Schlumberger, J. Endocrinol. Invest. 35, 40 (2012).
3) J. T. Kuikka et al., Nucl. Med. Commun. 19, 457 (1998).
4) E. L. Johnson et al., Nucl. Med. Biol. 22, 45 (1995).

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