Rapid imaging of tumor cell death in vivo using the c2a domain of synaptotagmin-I

Neves, A. A. et al. (2017) Rapid imaging of tumor cell death in vivo using the c2a domain of synaptotagmin-I. Journal of Nuclear Medicine, 58(6), pp. 881-887. (doi: 10.2967/jnumed.116.183004) (PMID:28209913)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lewis, Dr David
• Authors: Neves, A. A., Xie, B., Fawcett, S., Alam, I. S., Witney, T. H., de Backer, M. M., Summers, J., Hughes, W., McGuire, S., Soloviev, D., Miller, J., Howat, W. J., Hu, D.-e., Rodrigues, T. B., Lewis, D. Y., and Brindle, K. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Nuclear Medicine
• Publisher: Society of Nuclear Medicine
• ISSN: 0161-5505
• ISSN (Online): 2159-662X
• Published Online: 16 February 2017
• Copyright Holders: Copyright © 2017 The Society of Nuclear Medicine and Molecular Imaging
• First Published: First published in Journal of Nuclear Medicine 58(6):881-887
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher