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First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs
BACKGROUND: The [(177)Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [(177)Lu]Lu-DOTA-JR11, that demonstrated b...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313624/ https://www.ncbi.nlm.nih.gov/pubmed/37389800 http://dx.doi.org/10.1186/s41181-023-00197-0 |
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author | Handula, Maryana Beekman, Savanne Konijnenberg, Mark Stuurman, Debra de Ridder, Corrina Bruchertseifer, Frank Morgenstern, Alfred Denkova, Antonia de Blois, Erik Seimbille, Yann |
author_facet | Handula, Maryana Beekman, Savanne Konijnenberg, Mark Stuurman, Debra de Ridder, Corrina Bruchertseifer, Frank Morgenstern, Alfred Denkova, Antonia de Blois, Erik Seimbille, Yann |
author_sort | Handula, Maryana |
collection | PubMed |
description | BACKGROUND: The [(177)Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [(177)Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [(177)Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [(225)Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [(225)Ac]Ac(NO(3))(3) and [(177)Lu]LuCl(3). Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for (nat)La-DOTA-JR11, (nat)Lu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [(225)Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [(225)Ac]Ac-DOTA-JR11 and [(177)Lu]Lu-DOTA-JR11. RESULTS: [(225)Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [(225)Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [(177)Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with (nat)La and (nat)Lu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [(225)Ac]Ac-DOTA-JR11 than [(177)Lu]Lu-DOTA-JR11. CONCLUSION: [(225)Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [(177)Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [(225)Ac]Ac-DOTA-JR11. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41181-023-00197-0. |
format | Online Article Text |
id | pubmed-10313624 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-103136242023-07-02 First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs Handula, Maryana Beekman, Savanne Konijnenberg, Mark Stuurman, Debra de Ridder, Corrina Bruchertseifer, Frank Morgenstern, Alfred Denkova, Antonia de Blois, Erik Seimbille, Yann EJNMMI Radiopharm Chem Research Article BACKGROUND: The [(177)Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [(177)Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [(177)Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [(225)Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [(225)Ac]Ac(NO(3))(3) and [(177)Lu]LuCl(3). Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for (nat)La-DOTA-JR11, (nat)Lu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [(225)Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [(225)Ac]Ac-DOTA-JR11 and [(177)Lu]Lu-DOTA-JR11. RESULTS: [(225)Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [(225)Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [(177)Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with (nat)La and (nat)Lu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [(225)Ac]Ac-DOTA-JR11 than [(177)Lu]Lu-DOTA-JR11. CONCLUSION: [(225)Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [(177)Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [(225)Ac]Ac-DOTA-JR11. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41181-023-00197-0. Springer International Publishing 2023-06-30 /pmc/articles/PMC10313624/ /pubmed/37389800 http://dx.doi.org/10.1186/s41181-023-00197-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 | Research Article Handula, Maryana Beekman, Savanne Konijnenberg, Mark Stuurman, Debra de Ridder, Corrina Bruchertseifer, Frank Morgenstern, Alfred Denkova, Antonia de Blois, Erik Seimbille, Yann First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title | First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title_full | First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title_fullStr | First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title_full_unstemmed | First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title_short | First preclinical evaluation of [(225)Ac]Ac-DOTA-JR11 and comparison with [(177)Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs |
title_sort | first preclinical evaluation of [(225)ac]ac-dota-jr11 and comparison with [(177)lu]lu-dota-jr11, alpha versus beta radionuclide therapy of nets |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10313624/ https://www.ncbi.nlm.nih.gov/pubmed/37389800 http://dx.doi.org/10.1186/s41181-023-00197-0 |
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