Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I.

Abstract

Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. Methods: The capability of near-infrared fluorophore-labeled and 99mTc- and 111In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. Results: The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation (R > 0.9, P < 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. 99mTc-C2Am and 111In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. 99mTc-C2Am and 111In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. Conclusion: Given the favorable biodistribution profile of 99mTc- and 111In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.

• Authors: André A Neves, Bangwen Xie, Sarah Fawcett, Israt S Alam, Timothy H Witney, Maaike M de Backer, Julia Summers, William Hughes, Sarah McGuire, Dmitry Soloviev, Jodi Miller, William J Howat, De-En Hu, Tiago B Rodrigues, David Y Lewis, Kevin M Brindle
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 58 Issue 6 Pg. 881-887 (06 2017) ISSN: 1535-5667 [Electronic] United States
• PMID: 28209913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Biomarkers
• Radiopharmaceuticals
• Synaptotagmin I

Topics

• Animals
• Apoptosis
• Biomarkers (metabolism)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Molecular Imaging (methods)
• Neoplasms, Experimental (diagnostic imaging, metabolism, pathology)
• Positron-Emission Tomography (methods)
• Protein Domains
• Radiopharmaceuticals (pharmacokinetics)
• Synaptotagmin I (chemistry, pharmacokinetics)
• Tissue Distribution