RT Journal Article
SR Electronic
T1 Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 881
OP 887
DO 10.2967/jnumed.116.183004
VO 58
IS 6
A1 André A. Neves
A1 Bangwen Xie
A1 Sarah Fawcett
A1 Israt S. Alam
A1 Timothy H. Witney
A1 Maaike M. de Backer
A1 Julia Summers
A1 William Hughes
A1 Sarah McGuire
A1 Dmitry Soloviev
A1 Jodi Miller
A1 William J. Howat
A1 De-en Hu
A1 Tiago B. Rodrigues
A1 David Y. Lewis
A1 Kevin M. Brindle
YR 2017
UL http://jnm.snmjournals.org/content/58/6/881.abstract
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 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.