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

Neves, AA; Xie, B; Fawcett, S; Alam, IS; Witney, TH; de Backer, MM; Summers, J; ... Brindle, KM; + view all (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. 10.2967/jnumed.116.183004. Green open access

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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.

Type: Article
Title: Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I
Open access status: An open access version is available from UCL Discovery
DOI: 10.2967/jnumed.116.183004
Publisher version: http://dx.doi.org/10.2967/jnumed.116.183004
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Radiology, Nuclear Medicine & Medical Imaging, cell death, C2A, synaptotagmin, imaging, mouse, tumor, TARGETED CONTRAST AGENT, ANNEXIN-V, PET TRACER, APOPTOSIS, TC-99M, CHEMOTHERAPY, CANCER, BIOMARKERS, F-18-ML-10, DOSIMETRY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10049462
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