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A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

BACKGROUND: Our objective was to compare (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. METHODS: Trastuzumab...

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Detalles Bibliográficos
Autores principales: Chan, Conrad, Scollard, Deborah A, McLarty, Kristin, Smith, Serena, Reilly, Raymond M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250982/
https://www.ncbi.nlm.nih.gov/pubmed/22214307
http://dx.doi.org/10.1186/2191-219X-1-15
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author Chan, Conrad
Scollard, Deborah A
McLarty, Kristin
Smith, Serena
Reilly, Raymond M
author_facet Chan, Conrad
Scollard, Deborah A
McLarty, Kristin
Smith, Serena
Reilly, Raymond M
author_sort Chan, Conrad
collection PubMed
description BACKGROUND: Our objective was to compare (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. METHODS: Trastuzumab Fab were labeled with (111)In or (64)Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of (111)In- and (64)Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 10(6 )HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 10(5 )receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 10(5 )receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 10(6 )receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of (111)In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of (64)Cu-DOTA-trastuzumab Fab or irrelevant (111)In- or (64)Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. RESULTS: (111)In- and (64)Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (K(d )= 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using (111)In- and (64)Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for (111)In-DOTA-trastuzumab Fab than (111)In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of (64)Cu-DOTA-trastuzumab Fab was significantly higher than (64)Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both (111)In- and (64)Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for (64)Cu-DOTA-trastuzumab Fab than (111)In-DOTA-trastuzumab Fab. CONCLUSIONS: We conclude that (111)In-DOTA-trastuzumab Fab was more specific than (64)Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for (64)Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind (64)Cu may improve the association between T/B ratios and HER2 density for (64)Cu-labeled trastuzumab Fab.
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spelling pubmed-32509822012-02-03 A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT Chan, Conrad Scollard, Deborah A McLarty, Kristin Smith, Serena Reilly, Raymond M EJNMMI Res Original Research BACKGROUND: Our objective was to compare (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. METHODS: Trastuzumab Fab were labeled with (111)In or (64)Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of (111)In- and (64)Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 10(6 )HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 10(5 )receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 10(5 )receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 10(6 )receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of (111)In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of (64)Cu-DOTA-trastuzumab Fab or irrelevant (111)In- or (64)Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. RESULTS: (111)In- and (64)Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (K(d )= 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using (111)In- and (64)Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for (111)In-DOTA-trastuzumab Fab than (111)In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of (64)Cu-DOTA-trastuzumab Fab was significantly higher than (64)Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both (111)In- and (64)Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for (64)Cu-DOTA-trastuzumab Fab than (111)In-DOTA-trastuzumab Fab. CONCLUSIONS: We conclude that (111)In-DOTA-trastuzumab Fab was more specific than (64)Cu-DOTA-trastuzumab Fab for imaging HER2-positive tumors, especially those with low receptor density. This was due to higher levels of circulating radioactivity for (64)Cu-DOTA-trastuzumab Fab which disrupted the relationship between HER2 density and T/B ratios. Use of alternative chelators that more stably bind (64)Cu may improve the association between T/B ratios and HER2 density for (64)Cu-labeled trastuzumab Fab. Springer 2011-08-17 /pmc/articles/PMC3250982/ /pubmed/22214307 http://dx.doi.org/10.1186/2191-219X-1-15 Text en Copyright © 2011 Chan et al; licensee Springer. https://creativecommons.org/licenses/by/2.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 (https://creativecommons.org/licenses/by/2.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Chan, Conrad
Scollard, Deborah A
McLarty, Kristin
Smith, Serena
Reilly, Raymond M
A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title_full A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title_fullStr A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title_full_unstemmed A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title_short A comparison of (111)In- or (64)Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT
title_sort comparison of (111)in- or (64)cu-dota-trastuzumab fab fragments for imaging subcutaneous her2-positive tumor xenografts in athymic mice using microspect/ct or micropet/ct
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250982/
https://www.ncbi.nlm.nih.gov/pubmed/22214307
http://dx.doi.org/10.1186/2191-219X-1-15
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