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PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin
PURPOSE: To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460406/ https://www.ncbi.nlm.nih.gov/pubmed/34559266 http://dx.doi.org/10.1007/s00259-021-05559-x |
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author | Quigley, Neil Gerard Steiger, Katja Hoberück, Sebastian Czech, Norbert Zierke, Maximilian Alexander Kossatz, Susanne Pretze, Marc Richter, Frauke Weichert, Wilko Pox, Christian Kotzerke, Jörg Notni, Johannes |
author_facet | Quigley, Neil Gerard Steiger, Katja Hoberück, Sebastian Czech, Norbert Zierke, Maximilian Alexander Kossatz, Susanne Pretze, Marc Richter, Frauke Weichert, Wilko Pox, Christian Kotzerke, Jörg Notni, Johannes |
author_sort | Quigley, Neil Gerard |
collection | PubMed |
description | PURPOSE: To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)(3). Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. RESULTS: Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC(50) = 0.047 nM), selectivity over other subtypes (IC(50)-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUV(max) = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. CONCLUSIONS: Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05559-x. |
format | Online Article Text |
id | pubmed-8460406 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-84604062021-09-24 PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin Quigley, Neil Gerard Steiger, Katja Hoberück, Sebastian Czech, Norbert Zierke, Maximilian Alexander Kossatz, Susanne Pretze, Marc Richter, Frauke Weichert, Wilko Pox, Christian Kotzerke, Jörg Notni, Johannes Eur J Nucl Med Mol Imaging Original Article PURPOSE: To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)(3). Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. RESULTS: Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC(50) = 0.047 nM), selectivity over other subtypes (IC(50)-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUV(max) = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. CONCLUSIONS: Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-021-05559-x. Springer Berlin Heidelberg 2021-09-24 2022 /pmc/articles/PMC8460406/ /pubmed/34559266 http://dx.doi.org/10.1007/s00259-021-05559-x Text en © The Author(s) 2021 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 | Original Article Quigley, Neil Gerard Steiger, Katja Hoberück, Sebastian Czech, Norbert Zierke, Maximilian Alexander Kossatz, Susanne Pretze, Marc Richter, Frauke Weichert, Wilko Pox, Christian Kotzerke, Jörg Notni, Johannes PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title | PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title_full | PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title_fullStr | PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title_full_unstemmed | PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title_short | PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin |
title_sort | pet/ct imaging of head-and-neck and pancreatic cancer in humans by targeting the “cancer integrin” αvβ6 with ga-68-trivehexin |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460406/ https://www.ncbi.nlm.nih.gov/pubmed/34559266 http://dx.doi.org/10.1007/s00259-021-05559-x |
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