Complementary optical and nuclear imaging of caspase-3 activity using combined activatable and radio-labeled multimodality molecular probe

被引:36
作者
Lee, Hyeran [1 ]
Akers, Walter J. [1 ]
Cheney, Philip P. [1 ]
Edwards, W. Barry [1 ]
Liang, Kexian [1 ]
Culver, Joseph P. [1 ]
Achilefu, Samuel [1 ,2 ]
机构
[1] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA
[2] Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
optical imaging; nuclear imaging; scintigraphy; caspase-3; near-infrared fluorescence resonance energy transfer; IN-VIVO; RGD PEPTIDE; FLUORESCENCE;
D O I
10.1117/1.3207156
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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 Cu-64, 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 k(cat) and K-M of 0.55 +/- 0.01 s(-1) and 1.12 +/- 0.06 mu M, respectively. In mice, the initial fluorescence of LS498 is ten-fold less than control. Using radiolabeled Cu-64-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. (C) 2009 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3207156]
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页数:3
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