TY - JOUR
T1 - Rapid imaging of tumor cell death in vivo using the c2a domain of synaptotagmin-I
AU - Neves, A.A.
AU - Xie, B.
AU - Fawcett, S.
AU - Alam, I.S.
AU - Witney, Timothy H.
AU - De Backer, M.M.
AU - Summers, J.
AU - Hughes, W.
AU - McGuire, S.
AU - Soloviev, D.
AU - Miller, J.
AU - Howat, W.J.
AU - Hu, D.-E.
AU - Rodrigues, T.B.
AU - Lewis, D.Y.
AU - Brindle, K.M.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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 nearinfrared 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 fluorophorelabeled 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 4.3and 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. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.
AB - 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 nearinfrared 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 fluorophorelabeled 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 4.3and 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. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.
U2 - 10.2967/jnumed.116.183004
DO - 10.2967/jnumed.116.183004
M3 - Article
SN - 0161-5505
VL - 58
SP - 881
EP - 887
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 6
ER -
