1 July 2009 Complementary optical and nuclear imaging of caspase-3 activity using combined activatable and radio-labeled multimodality molecular probe
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J. of Biomedical Optics, 14(4), 040507 (2009). doi:10.1117/1.3207156
Abstract
Based on the capability of modulating fluorescence intensity by specific molecular events, we report a new multimodal optical-nuclear molecular probe with complementary reporting strategies. The molecular probe (LS498) consists of tetraazacyclododecanetetraacetic acid (DOTA) for chelating a radionuclide, a near-infrared fluorescent dye, and an efficient quencher dye. The two dyes are separated by a cleavable peptide substrate for caspase-3, a diagnostic enzyme that is upregulated in dying cells. LS498 is radiolabeled with 64Cu, a radionuclide used in positron emission tomography. In the native form, LS498 fluorescence is quenched until caspase-3 cleavage of the peptide substrate. Enzyme kinetics assay shows that LS498 is readily cleaved by caspase-3, with excellent enzyme kinetic parameters kcat and KM of 0.55±0.01 s-1 and 1.12±0.06 μM, respectively. In mice, the initial fluorescence of LS498 is ten-fold less than control. Using radiolabeled 64Cu-LS498 in a controlled and localized in-vivo model of caspase-3 activation, a time-dependent five-fold NIR fluorescence enhancement is observed, but radioactivity remains identical in caspase-3 positive and negative controls. These results demonstrate the feasibility of using radionuclide imaging for localizing and quantifying the distribution of molecular probes and optical imaging for reporting the functional status of diagnostic enzymes.
Hyeran Lee, Walter J. Akers, Philip P. Cheney, W. Barry Edwards, Kexiang Liang, Joseph P. Culver, Samuel Achilefu, "Complementary optical and nuclear imaging of caspase-3 activity using combined activatable and radio-labeled multimodality molecular probe," Journal of Biomedical Optics 14(4), 040507 (1 July 2009). http://dx.doi.org/10.1117/1.3207156
Submission: Received ; Accepted
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KEYWORDS
Luminescence

In vivo imaging

Positron emission tomography

Radio optics

Tumors

Optical imaging

Near infrared

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