The Current Situation and Prospect of Accelerator Produced Medical Radioisotopes

doi:10.7538/tws.2022.youxian.015

Abstract

Abstract: As one of the important ways to prepare radioisotopes, the role and status of accelerator produced nuclides have become increasingly prominent after entering the new century. In the present paper, a brief overview on development status of radioisotope preparation technology by accelerators at home and abroad was performed. In particular, the research progress of ¹⁸F, ⁶⁴Cu, ⁶⁸Ge/⁶⁸Ga, ⁸⁹Zr, ¹¹¹In, ²¹¹At, ²²⁵Ac and other important medical radioisotope preparation technologies are introduced. The application prospects of isotopes prepared by domestic accelerators are also prospected.

Key words: medical radioisotopes, accelerator production, radiopharmaleutical

摘要： 加速器制备核素以其独特的自身优势成为制备放射性同位素的重要方式之一，在进入新世纪后作用与地位日益突出。本文对国内外加速器制备医用放射同位素技术的发展现状进行了简要概述，着重分析了¹⁸F、⁶⁴Cu、⁶⁸Ge/⁶⁸Ga、⁸⁹Zr、¹¹¹In、²¹¹At、²²⁵Ac等重要医用放射性核素研究进展，并对我国加速器制备医用同位素的应用前景进行了展望。

关键词: 医用放射性同位素, 加速器制备, 放射性药物

LIU Ning, GAO Jing, YANG Yuanyou, LI Feize, LIAO Jiali. The Current Situation and Prospect of Accelerator Produced Medical Radioisotopes[J]. Journal of Isotopes, 2022, 35(5): 424-438.

刘宁, 高靖, 杨远友, 李飞泽, 廖家莉. 加速器制备医用放射性同位素的现状与展望[J]. 同位素, 2022, 35(5): 424-438.

References

［1］杨远友，李飞泽，廖家莉，等. 我国加速器同位素的研制与应用［J］. 同位素，2015，28 (4)：208-212.
Yang Yuanyou, Li Feize, Liao Jiali, et al. Development and application of accelerator isotopes in China［J］. Journal of Isotopes, 2015, 28(4): 208-212（in Chinese）.
［2］黄伟,梁积新,吴宇轩,等. 我国放射性同位素制备技术的发展［J］. 同位素，2019，32(3)：209-217.
Huang Wei, Liang Jixin, Wu Yuxuan, et al. Development of radioisotopes preparation technology in China［J］. Journal of Isotopes, 2019, 32(3): 209-217（in Chinese）.
［3］杨志. 中国放射性药物市场前景巨大［J］. 国防科技工业，2021，7：37-38.
Yang Zhi. China’s radiopharmaceutical market has huge prospects［J］. Defence Science Technology Industry, 2021, 7: 37-38（in Chinese）.
［4］Ruth T. Accelerating production of medical isotopes［J］. Nature, 2009, 457: 536-537.
［5］Gould P. Medical isotope shortage reaches crisis level［J］. Nature, 2009, 460: 312-313.
［6］Nagai Y, Hashimoto K, Hatukawa Y, et al. Generation of radioisotopes with accelerator neutrons by deuterons［J］. J Phys Soc Jpn, 2013, 82(6): 064201-1—064201-7.
［7］Nagai Y, Kawabata M, Sato N, et al. High thermo-separation efficiency of 99mTc from molten 100MoO₃ samples by repeated milking tests［J］. J Phys Soc Jpn, 2014, 83(8): 083201-1—083201-4.
［8］Nakai K, Takahashi N, Hatazawa J, et al. Feasibility studies towards future self-sufficient supply of the ⁹⁹Mo-^99mTc isotopes with Japanese accelerators［J］. Proc Jpn Acad Ser B, 2014, 90(10): 413-421.
［9］Dave S R, Samuel T A, Pucar D, et al. FDG PET/CT inevaluation of unusual cutaneous manifestations of breast cancer［J］. Clinical Nuclear Medicine, 2015, 40(1): 63-67.
［10］Lu Y Y, Chen J H, Liang J A, et al. ¹⁸F-FDG PET or PET/CT for detecting extensive disease in small-cell-lung cancer: a systematic review and meta-analysis［J］. Nuclear Medicine Communications, 2014, 35(7): 697-703.
［11］Teixeira S C, Peeters M J T V, Stokkel M P, et al. The role of PET/CT for nodal staging in primary stage Ⅱ/Ⅲ breast cancer patients［J］. Breast Cancer Management, 2015, 4(3): 165-174.
［12］王风,杨建华,谢卿,等. 医用回旋加速器生产正电子核素18F条件分析与优化［J］. 核技术,2018,41（2）:12-18.
Wang Feng, Yang Jianhua, Xie Qing, et al. Analysis and optimization of production conditions for 18F production using a medical cyclotron［J］. Nuclear Techniques, 2018, 41(2): 12-18（in Chinese）.
［13］霍焱,王荣福. 18F标记正电子药物研究现状与进展［J］. 核化学与放射化学,2015,37(5):376-380.
Huo Yan, Wang Rongfu. Current researches and progress on preparation of 18F labeled positron radiopharmacueticals［J］. Journal of Nuclear and Radiochemistry, 2015, 37(5): 376-380（in Chinese）.
［14］张天爵,樊明武,安世忠,等. CIAE回旋加速器及应用综述［J］. 原子能科学技术,2020,54(S1):275-292.
Zhang Tianjue, Fan Mingwu, An Shizhong, et al. Review of cyclotrons and their applications at CIAE［J］. Atomic Energy Science and Technology, 2020, 54(S1): 275-292（in Chinese）.
［15］刘宁,杨远友,金建南,等. 基于CS-30回旋加速器的同位素研制及应用［J］. 同位素,2012,25(3):189-192.
Liu Ning, Yang Yuanyou, Jin Jiannan, et al. Preparation of radioactive isotopes by CS-30 cyclotron and their applications［J］. Journal of Isotopes, 2012, 25(3): 189-192（in Chinese）.
［16］唐刚华. 正电子放射性核素的制备及其在药学领域中的应用［J］. 中国药物化学杂志,2003,13（1）:62-67.
Tang Ganghua. Preparation of positron-emitting radionuclide and its application to pharmaceutical fields［J］. Chinese Journal of Medicinal Chemistry, 2003, 13（1）: 62-67（in Chinese）.
［17］张锦明,田嘉禾. 国内正电子放射性药物发展现状简介［J］. 同位素,2006,19（4）:240-245.
Zhang Jinming, Tian Jiahe. The current state of PET radiopharmaceutical in China［J］. Journal of Isotopes, 2006, 19（4）: 240-245（in Chinese）.
［18］施孝金,张永信. ¹⁸F标记肿瘤显像剂的研究进展［J］. 世界临床药物,2009,30（30）:177-180.
Shi Xiaojin, Zhang Yongxin. The progress of ¹⁸F labeled tumor imaging agents［J］. World Clinical Drugs, 2009, 30（30）: 177-180（in Chinese）.
［19］梁积新,吴宇轩,罗志福.CIAE放射性同位素制备技术的发展［J］. 原子能科学技术,2020,54(S1):178-184.
Liang Jixin, Wu Yuxuan, Luo Zhifu. Development of radioisotope preparation technology at CIAE［J］. Atomic Energy Science and Technology, 2020, 54(S1): 178-184（in Chinese）.
［20］张锦明,杜进. 中国放射性药物制备的现状及展望［J］. 同位素,2019,32（3）:179-185.
Zhang Jinming, Du Jin. Preparation of radiopharmaceuticals in China: current status and prospects［J］. Journal of Isotopes, 2019, 32（3）: 179-185（in Chinese）.
［21］李艾芳,光红梅,王庆利. 美国近20年批准上市的放射性诊断药物的非临床研究评价概述［J］. 中国新药杂质,2021,30（10）:865-870.
Li Aifang, Guang Hongmei, Wang Qingli. An overview of nonclinical study and evaluation of diagnostic radiopharma ceuticals approved for marketing in the United States in the last two decades［J］. Chinese Journal of New Drugs, 2021, 30（10）: 865-870（in Chinese）.
［22］任超,黄政海,王源,等. Tau蛋白PET显像剂¹⁸F-flortaucipir的自动化合成及初步临床验证［J］.标记免疫分析与临床,2021,28（5）:842-846.
Ren Chao, Huang Zhenghai, Wang Yuan, et al. Automated synthesis and preliminary clinical validation of ¹⁸F-flortaucipir for Tau protein PET imaging［J］. Labeled Immunoassays and Clinical Medicine, 2021, 28（5）: 842-846（in Chinese）.
［23］Keam Susan J. Piflufolastat 18F: diagnostic first approval［J］. Molecular Diagnosis & Therapy, 2021, 25（5）: 1-10.
［24］穆博帅,徐洋,刘志博. 靶向PSMA放射性小分子药物研究进展［J］. 同位素,2021,34（6）:565-580.
Mu Boshuai, Xu Yang, Liu Zhibo. Research progress of PSMA-targeted small molecule drugs［J］. Journal of Isotopes, 2021, 34（6）: 565-580（in Chinese）.
［25］Zlatopolakiy B D, Endepols H, Krapf P, et al. Discovery of 18F-JK-PSMA-7, a PET probe for the detection of small PSMA-postive lesions［J］. Journal of Nuclear Medicine, 2019, 60(6): 817-823.
［26］Teli Liu, Chen Liu, Xiaoxia Xu, et al. Preclinical evaluation and pilot clinical study of AlF-¹⁸F-PSMA-BCH for prostate cancer PET imaging［J］. Journal of Nuclear Medicine, 2019, 60（9）: 1284-1292.
［27］Jalilian A R, Jr J O. The current status and future of theranostic copper-64 radiophormaceu-ticals［J］. Iranian Journal of Nuclear Medicine, 2017, 25(1): 1-10.
［28］Mcmillan D D, Maeda J, Bell J J, et al. Validation of ⁶⁴Cu-ATSM damaging DNA via high-LET Auger electron emission［J］. Journal of Radiation Research, 2015, 56(5): 784-791.
［29］Follacchio G A, De Feo M S, De Vincentis G, et al. Radiopharmaceuticals labelled with copper ra-dionuclides: Clinical results in human beings［J］.Current Radiopharmaceuticals, 2018, 11(1): 22-33.
［30］Vimalnath K V, Rajeswari A, Chirayil V, et al. Studies on preparation of ⁶⁴Cu using (n,γ) route of reactor production using medium flux research reactor india［J］. Journal of Radioanalytical and Nuclear Chemistry, 2011, 290(1): 221-225.
［31］Thisgaard H, Jensen M, Eelema D R. Medium to large scale radio isotope production for targeted radio therapy using a smal PET cyclotron［J］. Applied Radion and Isotopes, 2011, 69: 1-7.
［32］Ometakova J, Rajec P, Csiba V, et al. Automated production of ⁶⁴Cu prepared by 18 MeV cyclotron［J］. J Radioanal Nucl Chem, 2012, 293（1）: 217-222.
［33］孙夕林,闫龙天,王凯,等. 医用回旋加速器的⁶⁴Cu高效制备［J］. 现代生物医学进展,2016,16(19):3783-3787.
Sun Xilin, Yan Longtian, Wang Kai, et al. Medical cyclotron production of ⁶⁴Cu［J］. Progress in Modern Biomedicine, 2016, 16(19): 3783-3787（in Chinese）.
［34］朱华,王风,刘特立,等. 新型固体靶核素⁶⁴Cu的生产、质控及microPET［J］. 中华核医学与分子影像杂志,2018,38(12):797-800.
Zhu Hua, Wang Feng, Liu Teli, et al. Production, quality control and micro PET analysis of novel solid-target based radionuclide ⁶⁴Cu［J］. Chinese Journal of Nuclear Medicine and Molecular Imaging, 2018, 38(12): 797-800（in Chinese）.
［35］温凯,马承伟,段菲,等. 基于C30加速器的⁶⁴Cu核素制备工艺［J］. 原子能科学技术,2021,55（10）:1894-1900.
Wen Kai, Ma Chengwei, Duan Fei, et al. Preparation process of ⁶⁴Cu nuclide based on C30 cyclotron［J］. Atomic Energy Science and Technology, 2021, 55（10）: 1894-1900（in Chinese）.
［36］李彦峰,王钝. Copper Cu 64 dotatate（Detectnet）［J］. 中国药物化学杂志,2021,31（10）:861.
Li Yanfeng, Wang Dun. Copper ⁶⁴Cu dotatate（Detectnet）［J］. Chinese Journal of Medicinal Chemistry, 2021, 31（10）: 861(in Chinese).
［37］赵海龙,李洪玉. 肿瘤诊断⁶⁴Cu标记药物临床研究进展［J］. 同位素,2021,34（1）:79-88.
Zhao Hailong, Li Hongyu. Research progress of ⁶⁴Cu-radiopharmaceuticals in clinical trial for tumor diagnosis［J］. Journal of Isotopes, 2021, 34（1）: 79-88（in Chinese）.
［38］Grubmuller B, Baum R P, Capasso E, et al. ⁶⁴Cu-PSMA-617 PET/CT imaging of prostate adenocarcinoma: first in-human studies［J］.Cancer Biother Radiopharm, 2016, 31(8): 277-286.
［39］Carlos D J, Beijer B, Bauder-wust U, et al. Development of novel PSMA ligands for imaging and therapy with copper isotopes［J］. Journal of Nuclear Medicine, 2020, 61(1): 70-79.
［40］Liu T, Liu C, Zhang Z, et al. ⁶⁴Cu-PSMA-BCH: a new radiotracer for delayed PET imaging of prostate cancer［J］. European Journal of Nu-Clear Medicine and Molecular Imaging, 2021, 48（13）: 1-9.
［41］廖光星,李宁,何正中,等. 金属正电子核素标记的⁶⁴Cu-ATSM药物研究进展［J］. 中国医疗设备,2021,36(8):165-169.
Liao Guangxing, Li Ning, He Zhengzhong, et al. Research progress of ⁶⁴Cu-ATSM drugs labeled with metal positron nuclide［J］. China Medical Devices, 2021, 36(8): 165-169（in Chinese）.
［42］杨春慧,梁积新,沈浪涛,等. ⁶⁸Ga标记放射性药物的制备及应用研究进展［J］. 同位素,2017,30（3）:209-218.
Yang Chunhui, Liang Jixin, Shen Langtao, et al. Progress of preparation and applications of ⁶⁸Ga labelled radiopharmaceuticals［J］. Journal of Isotopes, 2017, 30（3）: 209-218（in Chinese）.
［43］黄钱焕,潘栋辉,徐宇平,等. ⁶⁸Ge/⁶⁸Ga发生器的临床应用［J］. 同位素,2017,30(4）:270-275.
Huang Qianhuan, Pan Donghui, Xu Yuping, et al. Application of the ⁶⁸Ge/⁶⁸Ga generator in clinic［J］. Journal of Isotopes, 2017, 30(4）: 270-275（in Chinese）.
［44］沈亦佳,傅红宇,罗文博,等. 电沉积法制备加速器生产⁶⁸Ge用镓镍固体靶［J］. 同位素,2014,27（1）:50-54.
Shen Yijia, Fu Hongyu, Luo Wenbo, et al. Preparation of Ga/Ni solid target for cyclotron-produced ⁶⁸Ge by electro deposition［J］. Journal of Isotopes, 2014, 27（1）: 50-54（in Chinese）.
［45］Meinken G E, Kurczak S, Mausner L F, et al. Production of high specific ativity ⁶⁸Ge at Brookhaven National Laboratary［J］. J Radioanal Nucl Chem, 2005, 263: 553-557.
［46］Jonathan M, Fitzsimmons, Mausner L. Development of a production scale purification of ⁶⁸Ge from irradiated gallium metal［J］. Radiochim Acta, 2015, 103(2): 117-123.
［47］郭志德,张现忠,杜进. ⁶⁸Ga标记药物研究进展［J］. 同位素,2019,32(5）:360-374.
Guo Zhide, Zhang Xianzhong, Du Jin. The research progress of ⁶⁸Ga generator and ⁶⁸Ga radiopharmaceuticals［J］. Journal of Isotopes, 2019, 32(5): 360-374（in Chinese）.
［48］Carlucci G, Ippisch R, Slavik R, et al. ⁶⁸Ga-PSMA-11 NDA approval: a novel and successful academic partnership［J］. The Journal of Nuclear Medicine, 2021, 62（2）: 149-155.
［49］Benesova M, Schafer M, Buder-wust U, et al. Preclinical evaluation of tailor-made DOTA conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of pros-tate cancer［J］. Journal of Nuclear Medicine, 2015, 56(6): 914-920.
［50］Duan X, Cao Z, Zhu H, et al. ⁶⁸Ga-labled ODAP-urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent［J］. European Journal of Nuclear Medicine and Molecular Imaging, 2021, 48（ Issue prepublish ）: 1-11.
［51］Jalilian A R, Osso J A. Production, applications and status of zirconium-89 immunoPET agents［J］. J Radioanal Nucl Chem, 2017, 314(1): 7-21.
［52］Zweit J, Downey S, Sharma H, et al. Production of no-carrier-added zirconium-89 for positron emission tomography［J］. Appl Radiat Isot, 1991, 42（2）: 199-201.
［53］Holland J P, Sheh Y, Lewis J S. Standardized methods for the production of high specific-activity zirconium-89［J］. Nuclear Medicine and Biology, 2009, 36（7）: 729-739.
［54］Tang Yu, Li Shuntao, Yang Yuanyou, et al. A simple and convenient method for production of Zr-89 with high purity［J］. Appl Radiat Isot, 2016, 118: 326-330.
［55］吴宇轩,梁积新,沈亦佳,等. Cyclone-30加速器制备⁸⁹Zr的工艺研究［M］∥中国原子能科学研究院年报. 北京:中国原子能出版社,2018.
［56］Jauw Y W S, Zijlstra J M, Jong D, et al. Performance of⁸⁹Zr-labeled-rituximab-PET as an imaging biomarker to assess CD20 targeting: a pilot study in patients with relapsed/refractory diffuse large B cell lymphoma［J］. PLoS One, 2017, 12: 828.
［57］Bensch F, Lamberts L E, Smeenk M M, et al.⁸⁹Zr-lumretuzumab PET imaging before and during HER₃ antibody lumretuzumab treatment in patients with solid tumors［J］. Clin Cancer Res, 2017, 23: 6128-6137.
［58］Pandit-Taskar N, O’Donoghue J A, Morris M J, et al. A phase Ⅰ/Ⅱ study for analytic validation of ⁸⁹Zr-J591 immunoPET as a molecular imaging agent for metastatic prostate cancer［J］. Clin Cancer Res, 2015, 21: 5277-5285.
［59］Kang L, Jiang D, England C G, et al. Immuno PET imaging of CD38 in murine lymphoma models using ⁸⁹Zr-labeled daratumumab［J］. Eur J Nucl Med Mol Imaging, 2018, 45: 1372-1381.
［60］England C G, Jiang D, Huang P, et al. ⁸⁹Zr-labeled nivolumab for imaging of T-cell infiltrationin a humanized murine model of lung cancer［J］. Eur J Nucl Med Mol Imaging, 2018, 45: 110-120.
［61］Tang Y, Hu Y, Yang Y, et al. A radiopharmaceutical ［⁸⁹Zr］Zr-DFO-nimotuzumab for immunoPET with epidermal growth factor receptor expression in vivo［J］. Nucl Med Biol, 2019, 17: 23-31.
［62］Hindie E, Zanotti-Fregonara P, Quinto M A, et al. Dose deposits from ⁹⁰Y, ¹⁷⁷Lu, ¹¹¹In, and ¹⁶¹Tb in Micrometastases of various sizes: implications for radiopharmaceutical therapy［J］. J Nucl Med, 2016, 57: 759-764.
［63］Kassis A I. Molecular and cellular radiobiological effects of Auger emitting radionuclides［J］. Radiat Prot Dosimetry, 2011, 143: 241-247.
［64］Lahiri S, Maiti M, Ghosh K. Production and separation of In-111: an important radionuclide in life sciences: a mini review［J］. J Radioanal Nucl Chem, 2013, 297(3): 309-318.
［65］Jing Gao, Zhonghui Liao, Weihao Liu, et al. Simple and efficient method for producing high radionuclidic purity ¹¹¹In using enriched 112Cd target［J］. Appl Radiat Isot, 2021, 176: 109828.
［66］王凡,樊红强,肖伦,等. ¹¹¹In-DTPA-octreotide的标记条件研究及初步动物实验［J］. 同位素,1997,10(1):16-20.
Wang Fan, Fan Hongqiang, Xiao Lun, et al. Labeling study on ¹¹¹In-octreotideand primary animal tests［J］. Journal of Isotopes, 1997, 10(1): 16-20（in Chinese）.
［67］刘正浩,唐志刚. 从辐照后的镉靶中分离¹¹¹In［J］. 核化学与放射化学,2000,22(4):248-251.
Liu Zhenghao, Tang Zhigang. Separation of¹¹¹In from irradiated cadmium target［J］. Journal of Nuclear and Radiochemistry, 2000, 22(4): 248-251（in Chinese）.
［68］陈玉清,罗文博,李光,等. 萃取色层法从加速器辐照的镉靶中提取¹¹¹In［J］. 同位素,2013,26(1):42-47.
Chen Yuqing, Luo Wenbo, Li Guang, et al. Separation of ¹¹¹In from cyclotron irradiated Cd target with extraction chromatographic method［J］. Journal of Isotopes, 2013, 26(1): 42-47（in Chinese）.
［69］李顺涛,刘宁,杨远友,等. CS-30回旋加速器制备¹¹¹In［J］. 核化学与放射化学,2015,37(6):407-408.
Li Shuntao, Liu Ning, Yang Yuanyou, et al.Preparation of ¹¹¹In on CS-30 cyclotron［J］. Journal of Nuclear and Radiochemistry, 2015, 37(6): 407-408（in Chinese）.
［70］Holloway C M, Scollard D A, Caldwell C B, et al. Phase I trial of intraoperative detection of tumor margins in patients with HER2-positive carcinoma of the breast following administration of ¹¹¹In-DTPA-trastuzumab Fab fragments［J］. Nucl Med Biol, 2013, 40: 630-637.
［71］Mix M, Reichel K, Stoykow C, et al. Performance of ¹¹¹In-labelled PSMA ligand in patients with nodal metastatic prostate cancer: correlation between tracer uptake and histopathology from lymphadenectomy［J］. Eur J Nucl Med Mol Imaging, 2018, 45: 2062-2070.
［72］Nagengast W B, Hooge M N, van Straten E M, et al. VEGF-SPECT with¹¹¹In-bevacizumab in stage Ⅲ/Ⅳ melanoma patients［J］. Eur J Cancer, 2011, 47: 1595-1602.
［73］Kentaro F, Atsushi B T, Hitomi S, et al. In-111-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis［J］. Ann Nucl Med, 2020, 34(1): 13-23.
［74］朱华,李囡,林新峰,等. ¹¹¹In-CCPM-RGD纳米粒子的合成及其双模态分子显像研究［J］. 化学学报, 2014,72:427-432.
Zhu Hua, Li Nan, Lin Xinfeng, et al. Design and synthesis of¹¹¹In-CCPM-RGD nanoparticles for dual-modality molecular imaging［J］. Acta Chimica Sinica, 2014, 72: 427-432（in Chinese）.
［75］朱华,李囡,张宏,等. ¹¹¹In-DOTA-mAb109单克隆抗体探针的制备及其分子显像的研究［J］. 化学学报,2015,73:36-40.
Zhu Hua, Li Nan, Zhang Hong, et al. Synthesis and evaluation of ¹¹¹In-DOTA-mAb 109 monoclonal antibody for potential SPECT molecular imaging［J］. Acta Chimica Sinica, 2015, 73: 36-40（in Chinese）.
［76］Tang Y, Liu W H, Li F Z, et al. Indium-111 labeled bleomycin for targeting diagnosis and therapy of liver tumor: optimized preparation, biodistribution and SPECT imaging with xenograft models［J］. J. Radioanal Nucl Chem, 2019, 322(2): 545-551.
［77］Zhonghui Liao, Feize Li, Yu Tang, et al. Preliminary in vitro comparison of ¹¹¹In and ¹³¹I labeled nimotuzumabs［J］. J Radioanal Nucl Chem, 2021, 328: 527-537.
［78］刘宁,马欢,杨远友,等. α核素肿瘤靶向治疗药物研究的进展与挑战［J］. 核化学与放射化学,2015,37（5）:367-376.
Liu Ning, Ma Huan, Yang Yuanyou, et al. Progress of α-emitters for Tumor Targeted Radiotherapy［J］. Journal of Nuclear and Radiochemistry, 2015, 37（5）: 367-376（in Chinese）.
［79］周懋伦,金建南,张叔渊,等. 211At的制备及其质量控制［J］. 四川大学学报（自然科学版）,1986,9(3):84-92.
Zhou Maolun, Jin Jiannan, Zhang Shuyuan, et al. The production of 211At and its quality control［J］. Journal of Sichuan University(Natural Science Edition), 1986, 9(3): 84-92（in Chinese）.
［80］Zona C, Bonardi M L, Groppi F, et al. Wet-chemistry method for the separation of no-carrier-added At-211/Po-211g from Bi-209 target irradiated by alpha-beam in cyclotron［J］. J Radioanal Nucl Chem, 2008, 276(3): 819-824.
［81］Martin T M, Bhakta V, Al-Harbi A, et al. Preliminary production of ²¹¹At at the Texas A&M University Cyclotron Institute［J］. Health Phys, 2014, 107(1): 1-9.
［82］Mickal B, Franois G, Cyrille A, et al. Feasibility of the radioastatination of a monoclonal antibody with astatine-211 purified by wet extraction［J］. J Labelled Comp Radiopharm, 2008, 51(11): 379-383.
［83］Dziawer L, Kozminski P, Meczynska-Wielgosz S, et al. Gold nanoparticle bioconjugates labelled with ²¹¹At for targeted alpha therapy［J］. RSC Advances, 2017, 7(65): 41024-41032.
［84］Kennel S J, Mirzadeh S, Eckelman W C, et al. Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At［J］. Radiation Research, 2002, 157(6): 633-641.
［85］Li Yawen, Hamlin Donald K, Chyan Ming-Kuan, et al. cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies［J］. PLoS One, 2018, 13(10): 0205135.
［86］Sofia H L F, Brian W M, Tom A B, et al. Alpha-imaging confirmed efficient targeting of CD45-positive cells after ²¹¹At-radioimmunotherapy for hematopoietic cell transplantation［J］. J Nucl Med, 2015, 56(11): 1766-1773.
［87］Johnnie J O, Tom B, Aimee K, et al. Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model［J］. Blood, 2013, 121(18): 3759-10667.
［88］Hallqvist A, Albertsson P, Hultborn R, et al. Intraperitoneal alpha-emitting radio immunotherapy with Astatine-211 in relapsed ovarian cancer; long-term follow-up with individual absorbed dose estimations［J］. J Nucl Med, 2019, 50（1）: S24-S25.
［89］Andersson H, Cederkrantz E, Back T, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab′)2-a phase I study［J］. J Nucl Med, 2009, 50(7) : 1153-1160.
［90］Zalutsky M R, Reardon D A, Akabani G, et al. Clinical experience with particle-emitting -sup 211At: treatment of recurrent brain tumor patients with sup 211At-labeled chimeric antitenascin monoclonal antibody ⁸¹C₆［J］. J Nucl Med, 2008, 49(1) : 30-38.
［91］Sudo H, Tsuji A B, Sugyo A, et al. Preclinical evaluation of the acute radiotoxicity of the alpha-emitting molecular-targeted therapeutic agent 211At-MABG for the treatment of malignant pheochromocy-toma in normal mice［J］. Transl Oncol, 2019, 12（7）: 879-888.
［92］O’Steen S, Comstock M L, Orozco J J, et al. The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model［J］. Blood, 2019, 134（15）: 1247-1256.
［93］Weihao Liu, Yu Tang, Huan Ma ,et al. Astatine-211 labelled a small molecule peptide: specific cell killing in vitro and targeted therapy in a nude-mouse model［J］. Radiochim Acta, 2020, 109（2）: 119-126.
［94］Zhao B, Qin S, Chai L, et al. Evaluation of astatine-211-labeled octreotide as a potential radiotherapeutic agent for NSCLC treatment［J］. Bioorg Med Chem, 2018, 26 (5): 1086-1091.
［95］王雷,吕银龙,王峰,等. 100 MeV回旋加速器生产医用²²⁵Ac核素的实验研究［J］. 原子能科学技术,2021,55（S1）:172-176.
Wang Lei, Lu Yinlong, Wang Feng, et al. Experimental study on production of medical nuclide ²²⁵Ac with 100 MeV cyclotron［J］. Atomic Energy Science and Technology, 2021, 55（S1）: 172-176（in Chinese）.
［96］陈俊艺,李银龙,王峰,等. 基于100 MeV质子回旋加速器与固相萃取方法制备与纯化靶向放射治疗核素锕-225［J］. 化学通报,2021,84（11）:1210-1218.
Chen Junyi, Li Yinlong, Wang Feng, et al, et al. Production and isolation of actinium-225 for targeted radiotherapy with a 100 MeV proton cyclotron and solid-phase extraction［J］. Chemistry, 2021, 84（11）: 1210-1218（in Chinese）.
［97］Robertson A K, Ramogida C F, Schaffer P, et al. Development of 225Ac radi-opharmaceuticals: TRIUMF perspectives and experiences［J］. Current Radiophalmaceuticals, 2018, 11(2): 1-17.
［98］Radchenko V, Engle J W, Wilson J J, et al. Application of ion exchange extraction chomatography to the separation of actinium from proton-irradiated thorium metal for analyti-cal purposes［J］. Journal of Chromatography A, 2015, 1380（1）: 55-63.
［99］Alliev R A, Ermolaev S V, Vasiliev A N, et al. Isolation of medicine-applicable actini-um-225 form thorium targetes irradiated by medium-energy protons［J］. Solvent Extraction and Ion Exchange, 2014, 32(5): 468-477.
［100］Zhuikov B L. Production of medical radionu-clides in Russia: Status and future-A review［J］. Applied Radiation and Isotopes, 2014, 84 (2): 48-56.
［101］Edyta C, Marek P, Agnieszka M, et al. Functionalized TiO₂ nanoparticles labelled with ²²⁵Ac for targeted alpha radionuclide therapy［J］. J Nanopart Res, 2018, 20(3): 75-83.
［102］Jurcic J G, Rosenblat T L, McDevitt M R, et al. Phase I trial of the targeted alpha-particle nano-generator actinium-225-(²²⁵Ac-lintuzumab) (anti-CD33; HuM195) in acute myeloid leukemia (AML)［J］. Journal of Clinical Oncology, 2011, 29 (15): 6516.
［103］Clemens K, Frank B, Frederik L G, et al. ²²⁵Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer［J］. J Nucl Med, 2016, 57(12): 1941-1944.
［104］Clemens K, Frank B, Hendrik R, et al. Targeted alpha-therapy of metastatic castration-resistant prostate cancer with ²²⁵Ac-PSMA-617: dosimetry estimate and empiric dose finding［J］. J Nucl Med, 2017, 58(10): 1624-1631.