Abstract
Abstract Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of C2Am, a phosphatidylserine-binding agent based on the C2A domain of synaptotagmin-I, for detecting tumor cell death in vivo. Methods: The capability of (99m)Technetium-, (111)Indium-labelled or near- infrared fluorophore-labelled derivatives of C2Am for imaging tumor cell death was evaluated in implanted and genetically engineered [Fig.1] mouse models of lymphoma and in a human colorectal xenograft, using single photon CT (SPECT) and planar near-infrared fluorescence imaging, respectively [1,2]. Results: (99m)Tc-C2Am and (111)In-C2Am showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the spleen and liver at 24 h after probe administration. (99m)Tc-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. A fluorophore-labelled C2Am derivative also showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (<5%). There was a significant correlation (R=0.9) between fluorescently labelled C2Am binding and histologic markers of cell death (cleaved caspase-3); no such correlation was observed with a site-directed mutant of C2Am that does not bind phosphatidylserine (iC2Am). Conclusions: Given the favorable biodistribution profile of radiolabelled C2Am derivatives, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation, particularly as PET tracers. We have initiated GMP manufacture and toxicology studies required for a Phase 1 trial.
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