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Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice

BACKGROUND: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with d...

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Autores principales: Cicone, Francesco, Gnesin, Silvano, Denoël, Thibaut, Stora, Thierry, van der Meulen, Nicholas P., Müller, Cristina, Vermeulen, Christiaan, Benešová, Martina, Köster, Ulli, Johnston, Karl, Amato, Ernesto, Auditore, Lucrezia, Coukos, George, Stabin, Michael, Schaefer, Niklaus, Viertl, David, Prior, John O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560118/
https://www.ncbi.nlm.nih.gov/pubmed/31187358
http://dx.doi.org/10.1186/s13550-019-0524-7
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author Cicone, Francesco
Gnesin, Silvano
Denoël, Thibaut
Stora, Thierry
van der Meulen, Nicholas P.
Müller, Cristina
Vermeulen, Christiaan
Benešová, Martina
Köster, Ulli
Johnston, Karl
Amato, Ernesto
Auditore, Lucrezia
Coukos, George
Stabin, Michael
Schaefer, Niklaus
Viertl, David
Prior, John O.
author_facet Cicone, Francesco
Gnesin, Silvano
Denoël, Thibaut
Stora, Thierry
van der Meulen, Nicholas P.
Müller, Cristina
Vermeulen, Christiaan
Benešová, Martina
Köster, Ulli
Johnston, Karl
Amato, Ernesto
Auditore, Lucrezia
Coukos, George
Stabin, Michael
Schaefer, Niklaus
Viertl, David
Prior, John O.
author_sort Cicone, Francesco
collection PubMed
description BACKGROUND: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter (152)Tb [(T(1/2) = 17.5 h, Eβ(+)mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to (152)Tb of a classical biodistribution experiment using the same antibody fragment labeled with (111)In. (152)Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with either (152)Tb or (111)In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of (152)Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of (152)Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of (111)In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. RESULTS: RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). CONCLUSIONS: MicroPET-based dosimetry of (152)Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern.
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spelling pubmed-65601182019-06-28 Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice Cicone, Francesco Gnesin, Silvano Denoël, Thibaut Stora, Thierry van der Meulen, Nicholas P. Müller, Cristina Vermeulen, Christiaan Benešová, Martina Köster, Ulli Johnston, Karl Amato, Ernesto Auditore, Lucrezia Coukos, George Stabin, Michael Schaefer, Niklaus Viertl, David Prior, John O. EJNMMI Res Original Research BACKGROUND: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter (152)Tb [(T(1/2) = 17.5 h, Eβ(+)mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to (152)Tb of a classical biodistribution experiment using the same antibody fragment labeled with (111)In. (152)Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with either (152)Tb or (111)In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of (152)Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of (152)Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of (111)In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. RESULTS: RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). CONCLUSIONS: MicroPET-based dosimetry of (152)Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern. Springer Berlin Heidelberg 2019-06-11 /pmc/articles/PMC6560118/ /pubmed/31187358 http://dx.doi.org/10.1186/s13550-019-0524-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Cicone, Francesco
Gnesin, Silvano
Denoël, Thibaut
Stora, Thierry
van der Meulen, Nicholas P.
Müller, Cristina
Vermeulen, Christiaan
Benešová, Martina
Köster, Ulli
Johnston, Karl
Amato, Ernesto
Auditore, Lucrezia
Coukos, George
Stabin, Michael
Schaefer, Niklaus
Viertl, David
Prior, John O.
Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title_full Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title_fullStr Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title_full_unstemmed Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title_short Internal radiation dosimetry of a (152)Tb-labeled antibody in tumor-bearing mice
title_sort internal radiation dosimetry of a (152)tb-labeled antibody in tumor-bearing mice
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560118/
https://www.ncbi.nlm.nih.gov/pubmed/31187358
http://dx.doi.org/10.1186/s13550-019-0524-7
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