William W Hunt, Mathew Long, Usama Kamil, Sunil Kellapatha, Wayne Noonan, Peter D Roselt, Brittany Emmerson, Michael S Hofman, Mohammad B Haskali
{"title":"放射合成临床级镥-177标记治疗剂的可扩展方案。","authors":"William W Hunt, Mathew Long, Usama Kamil, Sunil Kellapatha, Wayne Noonan, Peter D Roselt, Brittany Emmerson, Michael S Hofman, Mohammad B Haskali","doi":"10.1038/s41596-025-01176-2","DOIUrl":null,"url":null,"abstract":"<p><p>Theranostics utilizes tandem targeted diagnostic and therapeutic agents that are molecularly analogous. In a theranostic approach, the diagnostic agent is a tracer typically radiolabeled with a positron emission tomography radionuclide such as fluorine-18 or gallium-68. Utilizing the selectivity of the tracer, the therapeutic agent is subsequently radiolabeled with an ablative radionuclide such as the β<sup>-</sup> emitting lanthanide lutetium-177 (<sup>177</sup>Lu). <sup>177</sup>Lu is typically incorporated into theranostics using the chelators 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) that are used to prepare the <sup>177</sup>Lu-radiopharmaceutical [<sup>177</sup>Lu]Lu-DOTA-TATE, [<sup>177</sup>Lu]Lu-PSMA-617 and [<sup>177</sup>Lu]Lu-PSMA-I&T. Here we describe the scalable and validated production for these <sup>177</sup>Lu-radiopharmaceuticals and further include the necessary quality control protocols. The procedures can be generalized and support both carrier added and noncarrier added <sup>177</sup>Lu sources for use in a clinical setting. With robust procedures that accommodate <sup>177</sup>Lu activity levels from 5 to 100 GBq, the procedures ensure stability for up to 8 h postproduction and achieve an average activity yield of 98%. As proven in over 1,000 patient cycles, this methodology is adaptable to both centralized production facilities and regional centers, enabling versatile application across small and large-scale production settings.</p>","PeriodicalId":18901,"journal":{"name":"Nature Protocols","volume":" ","pages":""},"PeriodicalIF":13.1000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A scalable protocol for the radiosynthesis of clinical grade lutetium-177-labeled theranostic agents.\",\"authors\":\"William W Hunt, Mathew Long, Usama Kamil, Sunil Kellapatha, Wayne Noonan, Peter D Roselt, Brittany Emmerson, Michael S Hofman, Mohammad B Haskali\",\"doi\":\"10.1038/s41596-025-01176-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Theranostics utilizes tandem targeted diagnostic and therapeutic agents that are molecularly analogous. In a theranostic approach, the diagnostic agent is a tracer typically radiolabeled with a positron emission tomography radionuclide such as fluorine-18 or gallium-68. Utilizing the selectivity of the tracer, the therapeutic agent is subsequently radiolabeled with an ablative radionuclide such as the β<sup>-</sup> emitting lanthanide lutetium-177 (<sup>177</sup>Lu). <sup>177</sup>Lu is typically incorporated into theranostics using the chelators 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) that are used to prepare the <sup>177</sup>Lu-radiopharmaceutical [<sup>177</sup>Lu]Lu-DOTA-TATE, [<sup>177</sup>Lu]Lu-PSMA-617 and [<sup>177</sup>Lu]Lu-PSMA-I&T. Here we describe the scalable and validated production for these <sup>177</sup>Lu-radiopharmaceuticals and further include the necessary quality control protocols. The procedures can be generalized and support both carrier added and noncarrier added <sup>177</sup>Lu sources for use in a clinical setting. With robust procedures that accommodate <sup>177</sup>Lu activity levels from 5 to 100 GBq, the procedures ensure stability for up to 8 h postproduction and achieve an average activity yield of 98%. As proven in over 1,000 patient cycles, this methodology is adaptable to both centralized production facilities and regional centers, enabling versatile application across small and large-scale production settings.</p>\",\"PeriodicalId\":18901,\"journal\":{\"name\":\"Nature Protocols\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":13.1000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Protocols\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41596-025-01176-2\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Protocols","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41596-025-01176-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 0
摘要
治疗学利用分子相似的串联靶向诊断和治疗剂。在治疗方法中,诊断剂通常是用正电子发射断层扫描放射性核素(如氟-18或镓-68)进行放射性标记的示踪剂。利用示踪剂的选择性,治疗剂随后用烧蚀性放射性核素如β-发射镧系元素镥-177 (177Lu)进行放射性标记。177Lu通常使用螯合剂2,2',2'',2'' -(1,4,7,10-四氮杂环十二烷-1,4,7,10-四基)四乙酸(DOTA)和2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸(DOTAGA)掺入治疗药物中,用于制备177Lu-放射性药物[177Lu]Lu-DOTA-TATE, [177Lu] lu - pma -617和[177Lu] lu - pma - i&t。在这里,我们描述了这些177lu放射性药物的可扩展和经过验证的生产,并进一步包括必要的质量控制协议。该程序可以推广并支持添加载体和非添加载体的177Lu源,用于临床环境。该程序具有强大的程序,可容纳177Lu活性水平从5到100 GBq,该程序可确保长达8小时的后期稳定性,并实现98%的平均活性收率。经过1000多个患者周期的验证,该方法适用于集中式生产设施和区域中心,可在小型和大型生产环境中实现通用应用。
A scalable protocol for the radiosynthesis of clinical grade lutetium-177-labeled theranostic agents.
Theranostics utilizes tandem targeted diagnostic and therapeutic agents that are molecularly analogous. In a theranostic approach, the diagnostic agent is a tracer typically radiolabeled with a positron emission tomography radionuclide such as fluorine-18 or gallium-68. Utilizing the selectivity of the tracer, the therapeutic agent is subsequently radiolabeled with an ablative radionuclide such as the β- emitting lanthanide lutetium-177 (177Lu). 177Lu is typically incorporated into theranostics using the chelators 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) that are used to prepare the 177Lu-radiopharmaceutical [177Lu]Lu-DOTA-TATE, [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T. Here we describe the scalable and validated production for these 177Lu-radiopharmaceuticals and further include the necessary quality control protocols. The procedures can be generalized and support both carrier added and noncarrier added 177Lu sources for use in a clinical setting. With robust procedures that accommodate 177Lu activity levels from 5 to 100 GBq, the procedures ensure stability for up to 8 h postproduction and achieve an average activity yield of 98%. As proven in over 1,000 patient cycles, this methodology is adaptable to both centralized production facilities and regional centers, enabling versatile application across small and large-scale production settings.
期刊介绍:
Nature Protocols focuses on publishing protocols used to address significant biological and biomedical science research questions, including methods grounded in physics and chemistry with practical applications to biological problems. The journal caters to a primary audience of research scientists and, as such, exclusively publishes protocols with research applications. Protocols primarily aimed at influencing patient management and treatment decisions are not featured.
The specific techniques covered encompass a wide range, including but not limited to: Biochemistry, Cell biology, Cell culture, Chemical modification, Computational biology, Developmental biology, Epigenomics, Genetic analysis, Genetic modification, Genomics, Imaging, Immunology, Isolation, purification, and separation, Lipidomics, Metabolomics, Microbiology, Model organisms, Nanotechnology, Neuroscience, Nucleic-acid-based molecular biology, Pharmacology, Plant biology, Protein analysis, Proteomics, Spectroscopy, Structural biology, Synthetic chemistry, Tissue culture, Toxicology, and Virology.