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20 June 2022, Volume 35 Issue 3
Development Status and Prospect of Therapeutic Radiopharmaceuticals
GAO Jie, ZHENG Xiaobei, WANG Hongliang, LI Jianguo, ZHANG Lan, DU Jin
2022, 35(3):  151-163.  DOI: 10.7538/tws.2022.35.03.0151
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Therapeutic radiopharmaceuticals combine radionuclides with carriers. It uses radionuclide suitable radiation energy and range in the tissue, selectively concentrated irradiation of diseased tissue, while avoiding damage to normal tissue and achieving the desired therapeutic effect. It is mainly used for cancer treatment or relief of tumor-related symptoms. It is widely used in tumor diagnosis and treatment, myocardial imaging, early detection of neurodegenerative diseases and imaging diagnosis of inflammatory tissues. In recent years, with the rapid development of targeted ligands and the wide application of new medical nuclides, radiotherapeutic drugs have attracted more and more attention. At present, nuclides such as 153Sm, 89Sr, 223Ra, 90Y,  131I and 177Lu are commonly used to treat cancer, bone metastasis, liver cancer and thyroid cancer, and show exciting potential in treatment. The research on radiotherapeutic drugs is also increasing rapidly. The clinical application and development status of radiopharma in the market and in the research stage are briefly introduced, in order to provide reference for the research and development of radiopharma in China.
The Recent Research Development of 177Lu Radiopharmaceuticals
YANG Yuchuan, KAN Wentao, YANG Xia, WEI Hongyuan, ZHUO Liangang, WANG Jing, LIAO Wei, ZHAO Peng, WANG Guanquan
2022, 35(3):  164-178.  DOI: 10.7538/tws.2022.35.03.0164
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Various radionuclides emitting β-, α particles, auger electrons and conversion electrons have been applied in radiopharmaceuticals development and corresponding clinical evaluations. Among these applied radionuclides, lutetium-177 related radiopharmaceuticals have attracted tremendous interest from the scientific field. There were in total less than 20 publications throughout last century. However, there emerged nearly 1000 publications on 177Lu during the past ten years, indicating more efforts have been focus on 177Lu. This article will review the development of preclinical and clinical trials of 177Lu radiolabeled antibodies, peptides, nanoparticles as well as small molecules as therapeutical 177Lu radiopharmaceuticals dating to the recent two years. In the preclinical part, the targetting property, pharmacokinetics and biological property have been improved by drug design. In the clinical part, the reviewed radiopharmaceuticals displayed excellent safety, obvious inhibitory effect on tumor, obvious effects on prolonging the patient survival as well as improving the patients’ quality of life; qualified supplementary on the current clinical administration ways such as combined radionuclide therapy, chemo-immuno-radiotherapy, radiotheranostics and seperated administrations; supplementary on the human dosimetry data such as first-in-human dosimetry of gastrin-releasing peptide receptor antagonist [177Lu]Lu-RM2.
Research Status of Alpha-Emitting Radionuclide 225Ac: Preparation and Medical Application
ZHAO Ziyu, WEN Kai, MA Chengwei, CHU Haomiao, DUAN Fei, LI Guang, LI Zhongyong
2022, 35(3):  179-188.  DOI: 10.7538/tws.2022.35.03.0179
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Targeted alpha therapy (TAT) is a kind of nuclear medicine treatment based on alpha-emitting radionuclides and tumor-selective carrier molecules for targeted cancer cells. Due to its strong toxicity to targeted cancer cells and relatively less toxic to normal tissues, TAT has been a promising tumor treatment method. Attributed to its suitable half-life (9.9 d), unique decay properties (decay produceing 4α+2β particles), and suitable coordination, 225Ac has become one of the best choice for α nuclides in TAT. Studies have shown that the targeted 225Ac-radiopharmaceuticals exhibit excellent effectiveness on cancer treatment, but the preparation of 225Ac is facing research difficulties. This article summarized the properties of 225Ac nuclide, the status of the preparation process and 225Ac-radiopharmaceuticals for TAT. And prospects were proposed for the production process of 225Ac and its medical application. It is expected that the large-scale production of medical 225Ac will be standardized, and 225Ac-radiopharmaceuticals will be approved for tumor treatment in the future.
Study on Research and Development Status and Application of 90Y Microspheres
GAO Jie, LIU Xiaoming, ZHOU Wenhua, WANG Hongliang, ZHAO Xiaosheng, GE Qiang, LI Jianguo
2022, 35(3):  189-199.  DOI: 10.7538/tws.2022.35.03.0189
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With 90Y microspheres, radioactive microspheres are perfused to tumor feeding arteries through minimally invasive intervention, and then diffused and retained in small vessels of tumor terminals along with blood flow, so as to high selectively kill tumor cells by means of sustained release of high energy rays. 90Y microspheres are of important value in the local treatment of advanced liver cancer. At present, two types of 90Y microsphere products (SIR-Spheres- and TheraSpheres-) which have appeared on the market globally, have been clinically applied abroad for nearly twenty years, and have been incorporated into many authoritative norms and guidelines for the diagnosis and treatment of liver cancer. Since 2018, SIR-Spheres- and TheraSpheres- have gradually entered China and attracted the attention of domestic clinical experts, and have been incorporated into the latest relevant guidelines for the diagnosis and treatment of liver cancer in China. In 2022, SIR-Spheres-, as imported drugs, passed the approval of the National Medical Products Administration (NMPA) and were approved for listing to treat patients with surgically unresectable liver metastases of colorectal cancer after failure in standard treatment. At the same time, the first case of primary liver cancer has been treated by TheraSpheres-. 90Y carbon microspheres independently researched and developed in China show good clinical conversion potential. In order to more effectively carrying out clinical research and application of 90Y microsphere products in China and promote research and development innovation of similar products, this paper reviews types, the research and development status, clinical application and domestic development and outlook of 90Y microspheres, so as to provide reference for the research, development and application of 90Y microsphere drugs in China.
177Lu Radiolabeling of RM26 Modified with Oligo-Phenylene-Ethynylene and its Cellular Internalization
LIAO Wei, FU Huaxia, LI Xiangyu, KAN Wentao, YANG Xia, WANG Jing, ZHAO Peng, ZHUO Liangang, YANG Yuchuan, WEI Hongyuan
2022, 35(3):  200-208.  DOI: 10.7538/tws.2022.35.03.0200
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Gastrin releasing peptide receptor (GRPR) is overexpressed in various tumors, and these GRPR-positive tumors have successfully and widely been targeted with GRPR antagonists. To achieve a good therapeutic effectiveness and less radioactive dosage administration, high cellular internalization is required. The cellular internalization of agonists is better than that of antagonists, but the severe side effects of agonists restrict their applications. In this study, we hypothesized that introducing membrane penetrating oligo-phenylene-ethynylene (OPE) to GRPR antagonist RM26 could increase the cellular internalization of antagonists. Therefore, two multi-functional compounds NOTA-OPE-1-RM26 and NOTA-OPE-2-RM26 were synthesized and labelled with 177Lu with high efficiency. The 177Lu labelled compounds 177Lu-NOTA-OPEs-RM26 were stable in saline, dulbecco’s modified eagle medium (DMEM) and newborn bovine serum. The in vitro experimental results indicated that the introduction of OPE-1 slightly increased the cellular internalization of the radiolabelled compounds while OPE-2 significantly increased the cellular internalization. In addition, the introduction of OPEs did not change the specific binding ability of RM26. The investigations indicated that introducing the OPE to increase the internalization was feasible.
Preliminary Treatment Study of 211At and 131I Labeled Nimotuzumab in Tumor-bearing Mice
LIU Weihao, MA Huan, LI Feize, LI Hongyan, LAN Tu, LIAO Jiali, QIN Zhi, LIU Ning, YANG Yuanyou
2022, 35(3):  209-216.  DOI: 10.7538/tws.2022.35.03.0209
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Using nimotuzumab targeting epidermal growth factor receptor (EGFR) as carrier, we have established a one-step labeling process for 211At and 131I and performed a preliminary treatment study on tumor-bearing mice. The labeling rate both were about 95%, and related radiolabeling complexes could maintain stability in PBS and FBS. The distribution showed that tumor uptake was still maintained to (28.2±4.7) %ID·g-1 after 24 h at intratumoral injection. The therapeutic effect of 131I/211At -ATE-nimotuzumab in U87MG glioma-bearing nude mice was further evaluated. The two labeled drugs can significantly inhibit the growth of solid tumors in a dose-dependent manner with no significant effect on the body weight of mice, effectively prolonging the survival time of subjects. In comparison, the median survival time of tumor-bearing mice in the 211At-ATE-nimotuzumab group at 20 μCi was longer than that in the 131I-ATE-nimotuzumab group at 20 μCi (35 days and 31.6 days). This work further confirmed that the α-nuclide 211At has great potential in the research of radioactive targeted therapy, and can provide an important reference for the preclinical basic research of related drugs.
Preparation of No-Carrier-Added 177Lu by DGA Resin Assisted Cyclic Elution
ZHUO Liangang, YANG Yuchuan, YUE Haidong, XIONG Xiaoling, WANG Guanquan, WANG Hailin, YANG Lin, LIN Qingchuan, CHEN Qiping, TU Jun, WEI Hongyuan
2022, 35(3):  217-223.  DOI: 10.7538/tws.2022.35.03.0217
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A preparation process of No-Carrier-Added (NCA) 177Lu in China Mianyang Research Reactor (CMRR)was investigated. In this work, the key component of the process is DGA resin column which can adsorb Yb(Ⅲ) and Lu(Ⅲ) metal ions in the eluent was added to the purification process of 177Lu. The eluent “on-line” cyclic elution of lanthanide resin column was realized through special flow path connection. The tracer test showed that this technology can effectively reduce the volume of radioactive acid waste liquid generated from purification process of 177Lu. The technology was verified in three batches production, and the primary separation stage reduced the volume of waste liquid above 86%. The NCA 177Lu product prepared by cyclic elution process meets the quality requirements.
Preparation of Double Column Type 90Sr-90Y Generator Based on Polyantimonic Acid
GENG Zisheng, LI Bo, WU Jianrong, CHEN Yunming, LUO Ning, SUN Zhizhong, ZENG Junjie, ZHANG Jinsong
2022, 35(3):  224-232.  DOI: 10.7538/tws.2022.35.03.0224
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90Y is a significant medical radionuclide that can be labeled with monoclonal antibodies, microspheres and peptides for tumor therapy. In this study, inorganic adsorbent polyantimonic acid with excellent adsorption performance was prepared by vacuum freeze-drying method as the separation material, and the 90Sr-90Y generator was developed by the separation strategy of double column method and hold-back carrier method. The effect of reaction conditions, drying method and other factor on the preparation of polyantimonic acid were systematically investigated, and the optimized preparation process was obtained. The static adsorption capacity of polyantimonic acid for strontium is 121 mg/g, the adsorption equilibrium time is 4 h, and the dynamic adsorption capacity reached 73 mg/g. The adsorption performance of polyantimonic acid was significantly improved compared with previous reports. The separation of Sr and Y was carried out by the double column method with 89Sr as tracer, and the separation factor of Sr and Y could be increased to more than 107 after adding Sr hold-back carrier into the primary column eluent. This study puts forward new ideas and methods for the key technical problems in the preparation of 90Sr-90Y generator, and carries out experimental verification, which is of great significance to the preparation of 90Sr-90Y generator.