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Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer

BACKGROUND: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity...

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Autores principales: Kennedy, Gregory T., Azari, Feredun S., Nadeem, Bilal, Chang, Ashley, Segil, Alix, Bernstein, Elizabeth, Desphande, Charuhas, Kucharczuk, John C., Delikatny, Edward J., Singhal, Sunil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328188/
https://www.ncbi.nlm.nih.gov/pubmed/35903245
http://dx.doi.org/10.1155/2022/5447290
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author Kennedy, Gregory T.
Azari, Feredun S.
Nadeem, Bilal
Chang, Ashley
Segil, Alix
Bernstein, Elizabeth
Desphande, Charuhas
Kucharczuk, John C.
Delikatny, Edward J.
Singhal, Sunil
author_facet Kennedy, Gregory T.
Azari, Feredun S.
Nadeem, Bilal
Chang, Ashley
Segil, Alix
Bernstein, Elizabeth
Desphande, Charuhas
Kucharczuk, John C.
Delikatny, Edward J.
Singhal, Sunil
author_sort Kennedy, Gregory T.
collection PubMed
description BACKGROUND: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity-based tracer (VGT-309) for EC resection. METHODS: Murine (AKR, HNM007) and human (OE19) EC cell lines were screened for cathepsin expression by western blotting. In vitro binding affinity of VGT-309 was evaluated by fluorescence microscopy. Flank tumor models were developed by injecting EC cells into the flanks of BALB/c or athymic nude mice. Mice pretreated with a cathepsin inhibitor (JPM-OEt) were used to confirm on target binding. Animals were injected with 2 mg/kg VGT-309, underwent IMI, and were sacrificed 24 hours after injection. RESULTS: Cathepsins B, L, S, and X were expressed by EC cell lines, and all cell lines were labeled in vitro with VGT-309. Fluorescent signal was eliminated when cells were pretreated with JPM-OEt. On biodistribution analysis, VGT-309 accumulated in the liver, kidneys, and spleen without other organ involvement. VGT-309 selectively accumulated in flank allografts and xenografts, with mean signal-to-background ratio of 5.21 (IQR: 4.18-6.73) for flank allografts and 4.34 (IQR: 3.75-5.02) for flank xenografts. Fluorescence microscopy and histopathological analysis confirmed the selective accumulation of the tracer in tumors compared to background normal tissues. CONCLUSIONS: VGT-309 is an effective tracer for IMI of esophageal cancer. There is potential for clinical translation both as an adjunct to endoscopic detection and for complete removal of disease during esophagectomy.
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spelling pubmed-93281882022-07-27 Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer Kennedy, Gregory T. Azari, Feredun S. Nadeem, Bilal Chang, Ashley Segil, Alix Bernstein, Elizabeth Desphande, Charuhas Kucharczuk, John C. Delikatny, Edward J. Singhal, Sunil Mol Imaging Research Article BACKGROUND: Early detection and complete resection are important prognostic factors for esophageal cancer (EC). Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancer types. However, there are no EC-specific IMI tracers. We sought to test a cathepsin activity-based tracer (VGT-309) for EC resection. METHODS: Murine (AKR, HNM007) and human (OE19) EC cell lines were screened for cathepsin expression by western blotting. In vitro binding affinity of VGT-309 was evaluated by fluorescence microscopy. Flank tumor models were developed by injecting EC cells into the flanks of BALB/c or athymic nude mice. Mice pretreated with a cathepsin inhibitor (JPM-OEt) were used to confirm on target binding. Animals were injected with 2 mg/kg VGT-309, underwent IMI, and were sacrificed 24 hours after injection. RESULTS: Cathepsins B, L, S, and X were expressed by EC cell lines, and all cell lines were labeled in vitro with VGT-309. Fluorescent signal was eliminated when cells were pretreated with JPM-OEt. On biodistribution analysis, VGT-309 accumulated in the liver, kidneys, and spleen without other organ involvement. VGT-309 selectively accumulated in flank allografts and xenografts, with mean signal-to-background ratio of 5.21 (IQR: 4.18-6.73) for flank allografts and 4.34 (IQR: 3.75-5.02) for flank xenografts. Fluorescence microscopy and histopathological analysis confirmed the selective accumulation of the tracer in tumors compared to background normal tissues. CONCLUSIONS: VGT-309 is an effective tracer for IMI of esophageal cancer. There is potential for clinical translation both as an adjunct to endoscopic detection and for complete removal of disease during esophagectomy. Hindawi 2022-07-14 /pmc/articles/PMC9328188/ /pubmed/35903245 http://dx.doi.org/10.1155/2022/5447290 Text en Copyright © 2022 Gregory T. Kennedy et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Kennedy, Gregory T.
Azari, Feredun S.
Nadeem, Bilal
Chang, Ashley
Segil, Alix
Bernstein, Elizabeth
Desphande, Charuhas
Kucharczuk, John C.
Delikatny, Edward J.
Singhal, Sunil
Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title_full Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title_fullStr Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title_full_unstemmed Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title_short Preclinical Evaluation of an Activity-Based Probe for Intraoperative Imaging of Esophageal Cancer
title_sort preclinical evaluation of an activity-based probe for intraoperative imaging of esophageal cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9328188/
https://www.ncbi.nlm.nih.gov/pubmed/35903245
http://dx.doi.org/10.1155/2022/5447290
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