Accelerator Production of the Medical Isotope 211At and Monoclonal Antibody Labeling

doi:10.6023/A21060266

Acta Chimica Sinica ›› 2021, Vol. 79 ›› Issue (11): 1376-1384.DOI: 10.6023/A21060266 Previous Articles Next Articles

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加速器生产医用同位素²¹¹At及单抗标记

陈德胜^a^,^b^,^d, 刘葳豪^c, 黄清钢^a^,^b, 曹石巍^a^,^b, 田伟^a^,^b, 殷小杰^a^,^b, 谈存敏^a^,^b, 王洁茹^a^,^b^,^d^,^e, 初剑^a^,^d, 贾子萌^a^,^d, 程念炜^e, 高瑞勤^a^,^b, 吴晓蕾^a^,^b, 秦芝^a^,^b^,^*(), 范芳丽^a^,^b, 白静^a^,^b, 李飞泽^c, 廖家莉^c, 杨远友^c, 刘宁^c

a 中国科学院近代物理研究所兰州 730000
b 先进能源科学与技术广东省实验室惠州 516000
c 四川大学原子核科学技术研究所辐射物理及技术教育部重点实验室成都 610064
d 中国科学院大学核科学与技术学院北京 100049
e 兰州大学核科学与技术学院兰州 730000

投稿日期:2021-06-11 发布日期:2021-08-17
通讯作者: 秦芝
基金资助:
甘肃省引导科技创新发展专项资金资助项目

Accelerator Production of the Medical Isotope ²¹¹At and Monoclonal Antibody Labeling

Desheng Chen^a^,^b^,^d, Weihao Liu^c, Qinggang Huang^a^,^b, Shiwei Cao^a^,^b, Wei Tian^a^,^b, Xiaojie Yin^a^,^b, Cunmin Tan^a^,^b, Jieru Wang^a^,^b^,^d^,^e, Jian Chu^a^,^d, Zimeng Jia^a^,^d, Nianwei Cheng^e, Ruiqin Gao^a^,^b, Xiaolei Wu^a^,^b, Zhi Qin^a^,^b(), Fangli Fan^a^,^b, Jing Bai^a^,^b, Feize Li^c, Jiali Liao^c, Yuanyou Yang^c, Ning Liu^c

a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b Advanced Energy Science and Technology Guangdong Laboratory, Huizhou 516000, China
c Key Laboratory of Radiation Physics and Technology, Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, China
d School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing 100049, China
e School of Nuclear Science and Technology, Lanzhou University, Lanzhou 730000, China

Received:2021-06-11 Published:2021-08-17
Contact: Zhi Qin
Supported by:
Special Fund for Scientific and Technological Innovation and Development of Gansu Province of China

²¹¹At, with a half-life of 7.2 h, is an excellent radionuclide being investigated for use in targeted alpha therapy as the result of very high linear energy transfer. However, the production of ²¹¹At is limited by ²¹⁰At, because ²¹⁰At decays to produce long half-life (138.4 d) extremely toxic daughter ²¹⁰Po. The production of ²¹¹At via ²⁰⁹Bi(α,2n) nuclear reaction and ²¹⁰At via ²⁰⁹Bi(α,3n) nuclear reaction, as the energy of incident α-particle increases, the ratio of N(²¹⁰At)/N(²¹¹At) increases. In this research, the α-particle is provided by the Chinese Accelerator Driven Sub-critical System (ADS) Front-end Demo Linac at Institute of Modern Physics, Chinese Academy of Sciences. The technical process of ²¹¹At produced was studied systematically, including accelerator irradiation, separation by dry distillation method, quality analysis, and monoclonal antibody labeling. The bismuth targets were irradiated with α-particle by 28.18, 28.34, 28.48 28.92 MeV, and the target chamber adopts an inclined target with water cooling to improve the cooling effect. The dry distillation separation was carried out at a high temperature of 850 ℃, oxygen as the carrier gas, chloroform and ethanol as eluent, and the chloroform solution containing ²¹¹At was blow dry with nitrogen. The results showed that the total recovery of dry distillation separation of ²¹¹At reached 78.53%. After separation, the quality analysis of ²¹¹At was performed using a high-purity Ge-detector, alpha energy spectrometer, and mass spectrometer. The obtained solid ²¹¹At had high specific activity, radionuclide purity and chemical purity, where the content of impurity elements Bi, Cu, Zn, and Al was less than 100 ng/GBq, and the ratio of N(²¹⁰At)/N(²¹¹At) was less than 10^–5 when the incident particle energy is below 28.2 MeV. Finally, the labeling of ²¹¹At-nimotuzumab was realized through N-succinimidyl-3-(trimethylstannyl)benzoate, and the labeling rate was 94.86%. Based on this research, a set of simple and efficient separation methods was established, which laid a good foundation for the subsequent production and application of ²¹¹At in China.

Key words: accelerator, medical isotope, dry distillation method, ²¹¹At, labeling

Cite this article

Desheng Chen, Weihao Liu, Qinggang Huang, Shiwei Cao, Wei Tian, Xiaojie Yin, Cunmin Tan, Jieru Wang, Jian Chu, Zimeng Jia, Nianwei Cheng, Ruiqin Gao, Xiaolei Wu, Zhi Qin, Fangli Fan, Jing Bai, Feize Li, Jiali Liao, Yuanyou Yang, Ning Liu. Accelerator Production of the Medical Isotope ²¹¹At and Monoclonal Antibody Labeling[J]. Acta Chimica Sinica, 2021, 79(11): 1376-1384.

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靶材料	Bi-209	Bi-209	Bi-209	Bi-209
束流能量(MeV)	30.10	30.65	29.90	29.60
打靶数量	7	1	2	1
能损^a(MeV)/碳膜窗(40 μm)	1.42	1.40	1.42	1.42
能损^a(MeV)/冷却氦气 1.25 atm (65 mm)	0.34	0.33	0^b	0^a
剩余能量(MeV)	28.34	28.92	28.48	28.18
束流与靶面夹角(°)	15	15	15	15

靶材料	Bi-209	Bi-209	Bi-209	Bi-209
束流能量(MeV)	30.10	30.65	29.90	29.60
打靶数量	7	1	2	1
能损^a(MeV)/碳膜窗(40 μm)	1.42	1.40	1.42	1.42
能损^a(MeV)/冷却氦气 1.25 atm (65 mm)	0.34	0.33	0^b	0^a
剩余能量(MeV)	28.34	28.92	28.48	28.18
束流与靶面夹角(°)	15	15	15	15

序号	靶厚/(mg•cm^–2)	入射能量/MeV	平均流强/μA	辐照时间/h	EOB活度/MBq
序号	靶厚/(mg•cm^–2)	入射能量/MeV	平均流强/μA	辐照时间/h	理论值	实测值
1	10.18	28.34	1.88	1.20	45.97	43.83±4.26
2	13.83	28.34	2.03	1.03	50.57	41.98±3.62
3	15.71	28.34	1.90	1.13	54.11	49.49±2.88
4	17.48	28.34	1.95	2.05	103.78	118.82±7.08
5	19.89	28.34	2.05	2.01	107.78	61.78±3.63
6	15.43	28.34	1.85	2.26	105.69	109.89±6.34
7	9.97	28.34	2.07	2.04	83.91	85.97±4.96
8	10.18	28.92	2.05	1.50	76.31	88.83±5.16
9	19.07	28.48	7.07	1.83	344.97	73.36±1.81
10	18.55	28.48	8.18	4.08	889.78	314.61±3.47
11	19.05	28.18	10.02	4.08	993.87	351.18±4.12

序号	靶厚/(mg•cm^–2)	入射能量/MeV	平均流强/μA	辐照时间/h	EOB活度/MBq
序号	靶厚/(mg•cm^–2)	入射能量/MeV	平均流强/μA	辐照时间/h	理论值	实测值
1	10.18	28.34	1.88	1.20	45.97	43.83±4.26
2	13.83	28.34	2.03	1.03	50.57	41.98±3.62
3	15.71	28.34	1.90	1.13	54.11	49.49±2.88
4	17.48	28.34	1.95	2.05	103.78	118.82±7.08
5	19.89	28.34	2.05	2.01	107.78	61.78±3.63
6	15.43	28.34	1.85	2.26	105.69	109.89±6.34
7	9.97	28.34	2.07	2.04	83.91	85.97±4.96
8	10.18	28.92	2.05	1.50	76.31	88.83±5.16
9	19.07	28.48	7.07	1.83	344.97	73.36±1.81
10	18.55	28.48	8.18	4.08	889.78	314.61±3.47
11	19.05	28.18	10.02	4.08	993.87	351.18±4.12

靶序号	温度/℃	气流量/(mL•min^–1)	保温时间/min	洗涤液	洗涤液用量(mL)			收集率
靶序号	温度/℃	气流量/(mL•min^–1)	保温时间/min	洗涤液	一段	二段	三段	一段	二段	三段
1	850	15	15	CHCl₃	0.4	2.0	—	—	—	—
2	850	15	15	CHCl₃	0.4	1.0	—	—	—	—
3	850	15	15	CHCl₃	5.0	10.0	—	—	—	—
4	850	15	15	CHCl₃	4.0	5.0	—	54.85±8.22%	1.42±8.35%	—
5	850	08	15	CHCl₃	1.0	5.0	—	34.40±8.29%	3.51±8.28%	—
6	850	10	15	CHCl₃	1.0	5.0	—	27.73±8.17%	2.48±8.17%	—
7	850	15	15	C₂H₆O	0.4	1.0	—	39.45±8.15%	5.14±8.17%	—
8	850	15	25	C₂H₆O	0.8	1.0	—	41.63±8.22%	3.37±8.29%	—
9	850	15	20	CHCl₃	0.4	0.4	—	42.83±5.60%	4.53±5.93%	—
10	850	15	20	CHCl₃	0.4	0.4	—	44.71±5.82%	17.44±6.30%	—
11	850	15	20	CHCl₃	0.4	0.4	1.0	48.69±5.79%	15.86±6.36%	13.98±6.43%

加速器生产医用同位素²¹¹At及单抗标记

Accelerator Production of the Medical Isotope ²¹¹At and Monoclonal Antibody Labeling

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种态	At	AtO₂	HAtO
–ΔH_ads/(kJ•mol^–1)	124±5	83±5	47±5
ΔH_subl/(kJ•mol^–1)	148±25	106±30	56±30

能量(MeV)	N(²¹⁰At)/N(²¹¹At)
能量(MeV)	α能谱法	γ能谱法
28.18	7.07×10^–6	<5.73×10^–7
28.34	1.61×10^–5	4.19×10^–6
28.48	4.35×10^–5	1.42×10^–5
28.92	3.05×10^–4	1.38×10^–4

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t/h	PBS/%	FBS/%
3	94.25	87.34
6	92.73	86.42
12	85.71	76.71
24	79.31	73.87

t/h	PBS/%	FBS/%
3	94.25	87.34
6	92.73	86.42
12	85.71	76.71
24	79.31	73.87

加速器生产医用同位素211At及单抗标记