Abstract
In the era of personalized medicine, there is an urgent need for in vivo techniques able to sensitively detect and quantify molecular activities. Sensitive imaging of gamma rays is widely used; however, radioactive decay is a physical constant, and its signal is independent of biological interactions. Here, we introduce a framework of previously uncharacterized targeted and activatable probes that are excited by a nuclear decay–derived signal to identify and measure molecular signatures of disease. We accomplished this by using Cerenkov luminescence, the light produced by β-particle–emitting radionuclides such as clinical positron emission tomography (PET) tracers. Disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence. This approach reduces background signal compared to conventional fluorescence imaging. In addition to tumor identification from a conventional PET scan, we demonstrate the medical utility of our approach by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and represents a shift toward activatable nuclear medicine agents.
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Acknowledgements
We thank the staff of the Radiopharmacy at Memorial Sloan-Kettering Cancer Center (MSKCC). Scientific input was provided by M. McDevitt, N.V.K. Pillarsetty, P. Zanzonico, J. Holland and J. Lewis (of MSKCC, who also generously provided radiolabeled trastuzumab). D.L.J.T. and this work were supported by US National Institutes of Health (NIH) through the R25T Molecular Imaging Fellowship of the Molecular Imaging: Training for Oncology (MITO) Program (5R25CA096945-07; principal investigator H. Hricak). J.G. was supported by the US Department of Defense (PC111667), the Starr Cancer Consortium (I4-A427), NIH (1R01EB014944–01), the American Recovery and Reinvestment Act (73950) and the Louis V. Gerstner Young Investigator Award. Technical services provided by the Animal Imaging Core Facility were supported in part by grants from the NIH (R24 CA083084 and P30 CA008748). We thank R. Weissleder for suggestions and L. Cosgrave at MSKCC and N. Sela-Passwell of the Weizmann Institute of Science for their help.
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D.L.J.T. initiated the project, designed and performed experiments, analyzed the data and wrote the manuscript. B.J.B. assisted in quantitative modeling, and A.O. assisted with ex vivo experiments. J.G., as the principal investigator, contributed to the experimental design and manuscript preparation and initiated the project. All authors edited the manuscript.
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Thorek, D., Ogirala, A., Beattie, B. et al. Quantitative imaging of disease signatures through radioactive decay signal conversion. Nat Med 19, 1345–1350 (2013). https://doi.org/10.1038/nm.3323
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DOI: https://doi.org/10.1038/nm.3323
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