A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy
© 2023. The Author(s)..
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 [natLu]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 [177Lu]Lu-LuFL ([177Lu]21) and [177Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy.
RESULTS: LuFL (20) and [natLu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC50: 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC50: 6.69 ± 0.88 nM). In vitro cellular studies showed that 18F-/177Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [18F]/[177Lu]21 revealed higher tumor uptake and longer tumor retention than those of [68 Ga]/[177Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [177Lu]21 group, than for the control group and the [177Lu]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 18F- and 177Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:50 |
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| Enthalten in: |
European journal of nuclear medicine and molecular imaging - 50(2023), 8 vom: 17. Juli, Seite 2331-2341 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Tianhong [VerfasserIn] |
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| Links: |
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| Themen: |
BRH40Y9V1Q |
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| Anmerkungen: |
Date Completed 12.06.2023 Date Revised 01.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00259-023-06169-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353702811 |
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| 100 | 1 | |a Yang, Tianhong |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.06.2023 | ||
| 500 | |a Date Revised 01.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a METHODS: The precursor LuFL (20) and [natLu]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 [177Lu]Lu-LuFL ([177Lu]21) and [177Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy | ||
| 520 | |a RESULTS: LuFL (20) and [natLu]Lu-LuFL (21) demonstrated excellent binding affinity towards FAP (IC50: 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC50: 6.69 ± 0.88 nM). In vitro cellular studies showed that 18F-/177Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [18F]/[177Lu]21 revealed higher tumor uptake and longer tumor retention than those of [68 Ga]/[177Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [177Lu]21 group, than for the control group and the [177Lu]Lu-FAPI-04 group | ||
| 520 | |a 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 18F- and 177Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a FAP inhibitor | |
| 650 | 4 | |a Radiohybrid | |
| 650 | 4 | |a Silicon-fluoride-acceptor | |
| 650 | 4 | |a Theranostics | |
| 650 | 7 | |a Lutetium-177 |2 NLM | |
| 650 | 7 | |a BRH40Y9V1Q |2 NLM | |
| 650 | 7 | |a Fluorine-18 |2 NLM | |
| 650 | 7 | |a GZ5I74KB8G |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Fluorine Radioisotopes |2 NLM | |
| 650 | 7 | |a Gallium Radioisotopes |2 NLM | |
| 700 | 1 | |a Peng, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xingjin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dake |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Renbo |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jianbo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiangsong |e verfasserin |4 aut | |
| 700 | 1 | |a Zha, Zhihao |e verfasserin |4 aut | |
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