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A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy
PURPOSE: A series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68–labeled FAPI derivatives, was limited by the short nuclide half-life and product...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250256/ https://www.ncbi.nlm.nih.gov/pubmed/36864362 http://dx.doi.org/10.1007/s00259-023-06169-5 |
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author | Yang, Tianhong Peng, Lei Qiu, Jia He, Xingjin Zhang, Dake Wu, Renbo Liu, Jianbo Zhang, Xiangsong Zha, Zhihao |
author_facet | Yang, Tianhong Peng, Lei Qiu, Jia He, Xingjin Zhang, Dake Wu, Renbo Liu, Jianbo Zhang, Xiangsong Zha, Zhihao |
author_sort | Yang, Tianhong |
collection | PubMed |
description | PURPOSE: A series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68–labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics. METHODS: The precursor LuFL (20) and [(nat)Lu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [(177)Lu]Lu-LuFL ([(177)Lu]21) and [(177)Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy. RESULTS: LuFL (20) and [(nat)Lu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC(50): 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC(50): 6.69 ± 0.88 nM). In vitro cellular studies showed that (18)F-/(177)Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [(18)F]/[(177)Lu]21 revealed higher tumor uptake and longer tumor retention than those of [(68) Ga]/[(177)Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [(177)Lu]21 group, than for the control group and the [(177)Lu]Lu-FAPI-04 group. CONCLUSION: The novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with (18)F- and (177)Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06169-5. |
format | Online Article Text |
id | pubmed-10250256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-102502562023-06-10 A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy Yang, Tianhong Peng, Lei Qiu, Jia He, Xingjin Zhang, Dake Wu, Renbo Liu, Jianbo Zhang, Xiangsong Zha, Zhihao Eur J Nucl Med Mol Imaging Original Article PURPOSE: A series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68–labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics. METHODS: The precursor LuFL (20) and [(nat)Lu]Lu-LuFL (21) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [(177)Lu]Lu-LuFL ([(177)Lu]21) and [(177)Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy. RESULTS: LuFL (20) and [(nat)Lu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC(50): 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC(50): 6.69 ± 0.88 nM). In vitro cellular studies showed that (18)F-/(177)Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [(18)F]/[(177)Lu]21 revealed higher tumor uptake and longer tumor retention than those of [(68) Ga]/[(177)Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [(177)Lu]21 group, than for the control group and the [(177)Lu]Lu-FAPI-04 group. CONCLUSION: The novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with (18)F- and (177)Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06169-5. Springer Berlin Heidelberg 2023-03-03 2023 /pmc/articles/PMC10250256/ /pubmed/36864362 http://dx.doi.org/10.1007/s00259-023-06169-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Yang, Tianhong Peng, Lei Qiu, Jia He, Xingjin Zhang, Dake Wu, Renbo Liu, Jianbo Zhang, Xiangsong Zha, Zhihao A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title | A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title_full | A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title_fullStr | A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title_full_unstemmed | A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title_short | A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
title_sort | radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10250256/ https://www.ncbi.nlm.nih.gov/pubmed/36864362 http://dx.doi.org/10.1007/s00259-023-06169-5 |
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