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Rapid Imaging of Tumor Cell Death in vivo using the C2A domain of Synaptotagmin-I

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Neves, AA 
Xie, B 
Fawcett, S 
Alam, IS 
Witney, TH 


Cell death is an important target for imaging the early response of tumors to treatment. We describe here 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 99mTechnetium- and 111Indium-labeled derivatives of C2Am for imaging tumor cell death, using planar near infrared fluorescence (NIRF) imaging and single photon computed tomography (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 histological 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 non-specific retention in 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 two hours and 7.3× and 4.1× respectively at twenty-four hours after administration.

Conclusion: Given the favorable biodistribution profile of 99mTc- and 111In-labelled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.



animal imaging, molecular imaging, oncology: GI, oncology: lymphoma, optical, radioimmunoimaging, radiopharmaceuticals, SPECT, SPECT/CT, C2A synaptotagmin, cell death, phosphatidylserine, radionuclide fluorescence imaging, tumor

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Journal of Nuclear Medicine

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Society of Nuclear Medicine and Molecular Imaging
Cancer Research UK (C14303/A17197)
Cancer Research UK (CB4100)
This work was supported by a Cancer Research UK programme grant to K.M.B. S.F. was the recipient of a Ph.D. studentship from the Cambridge Biomedical Research Centre of the National Institute of Health Research with financial support from GlaxoSmithKline UK. T.B.R. was in receipt of Intra-European Marie Curie (FP7-PEOPLE-2009-IEF, Imaging Lymphoma) and Long-term EMBO (EMBO-ALT-1145-2009) fellowships.