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Quantitative imaging of disease signatures through radioactive decay signal conversion

Nature Medicine volume 19, pages 1345–1350 (2013)Cite this article

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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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Figure 1: The conventional PET tracer principle and the development of agents that fluorescently convert the Cerenkov radiation optical decay signal.
Figure 2: Comparison of the external excitation and Cerenkov luminescence excitation of fluorophore.
Figure 3: Multispectral and tandem Cerenkov-induced fluorescence emission for disease biomarker readout.
Figure 4: Detection and quantification of MMP-2 enzyme action using activatable SCIFI nanoparticles.

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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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Authors and Affiliations

  1. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Daniel L J Thorek, Anuja Ogirala & Jan Grimm

  2. Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Bradley J Beattie

  3. Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Jan Grimm

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  1. Daniel L J Thorek
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Contributions

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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Correspondence to Jan Grimm.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–6 and Supplementary Tables 1–2 (PDF 9242 kb)

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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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