Quantitative imaging of disease signatures through radioactive decay signal conversion

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature medicine (Impact Factor: 27.36). 09/2013; 19(10). DOI: 10.1038/nm.3323
Source: PubMed


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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Available from: Jan Grimm, Sep 26, 2014
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    • "The molecules of the unmodified probe (resazurin) absorb the light, causing a decrease of the intensity of Cerenkov luminescence. After in vivo reduction by viable cells they are converted into fluorescent molecules, which cause increasing of the light intensity due to secondary Cerenkovinduced fluorescence [10] [11]. As the result, an overall intensity of the observed light will be increased proportionally to the concentration of viable cells in the tissue of target (e.g. "
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    ABSTRACT: We present the synthesis and characterization of F18-labeled fluorinated derivatives of resazurin, a probe for cell viability. The compounds were prepared by direct fluorination of resazurin with diluted [F18]-F2 gas under acidic conditions. The fluorination occurs into the ortho-positions to the hydroxyl group producing various mono-, di-, and trifluorinated derivatives. The properties of the fluorinated resazurins are similar to the parent compound with the addition of fluorine leading to decreased pKa values and a bathochromic shift of the absorption maxima. The fluorinated resazurin derivatives can be used as probes for observation of cell viability in various cells, tissues and organs using a combination of positron emission tomography and direct optical imaging of Cerenkov luminescence.
    Journal of Fluorine Chemistry 08/2015; 178:136-141. DOI:10.1016/j.jfluchem.2015.07.017 · 1.95 Impact Factor
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    • "In addition to enabling Cerenkov optical imaging for intraoperative clinical use, tumor-specific clinical applied radiotracers have synergistic advantages for PET-based diagnostics and therapeutics. Thorek et al. reported that disease markers were detected using nanoparticles to produce secondary Cerenkov-induced fluorescence and could be applied to monitor other markers, representing a shift toward activatable nuclear medical agents 175. New approaches using clinical PET tracers to produce secondary Cerenkov-induced fluorescence provide us with the opportunity to adopt their use for surgical applications 175. "
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    ABSTRACT: Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.
    Theranostics 08/2014; 4(11):1072-1084. DOI:10.7150/thno.9899 · 8.02 Impact Factor
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    • "Type Aims Specific Target Models Luminescence Sources Instrument Reference C Detectrion of miRNA expression in cells Detection of let-7 expression Comparison with scintigraphy In vitro: pulmonary carcinoma hNIS-A549 cells Na131I ( -, 89.9%) IVIS Kinetic Yang et al. 2012 [14] C Cancer imaging of theranostic probes Synthesis of radioluminescence 198Au-doped nanocages Mice bearing EMT-6 breast cancer xenoraft tumor 198-Au nancages ( -, 98.9%) IVIS Lu- mina II XR Wang et al. 2013 [15] C Cancer imaging Evaluation of 89Zr -rituximab tracer for non-Hodgkin's lymphoma (NHL) Humanized transgenic mice expressing human CD20 89Zr – desferrioxaminerituximab ( + , 23%) IVIS Spec- trum Natarajan et al. 2013 [16] C Cancer Imaging Excitation of FITC, Cy5.5, Cy7, QD565, QD605, QD800, ICG. Imaging of tumor markers cRGD-QD605 targeting 3 integrin Imaging of matrix metallopep- tidase-2 enzymatic activity using gold nanopaarticles conjugate to FAM labeled peptides (IPVSLRSG) In vitro QDots impregnated matrigel pseudotumors Mice bearing Her2/neu- positive xenografts (BT-474) Mice bearing MMP-2- overexpressing xenografts (SCC7) Mice bearing MMP-2- underexpressing xenografts (BT20) 68Ga ( + , 88%) 18 F-FDG ( + , 97%) 89Zr-DFO- trastuzumab ( + , 23%) Not reported Thorek et al. 2013 [17] C Cancer imaging Develop of 68Ga superparamagnetic iron oxide nanoparticles (SPIONs) for multi-modal imaging: PET/MR/ Cerenkov Visualization ex-vivo of 68Ga- SPIONs in Sentinel Lymph Node (SLN) in rats 68Ga-SPIONs ( + , 88%) Andor iKon 934 M Madru et al. 2014 [18] T Cerenkov Lu- minescence Tomography Multi-view tomography with two mirrors obtained modelling of the optical photon propagation with the diffusion equation and reconstructing the optical emission source distribution iteratively with a preconditioned conjugate gradient method Validation with PET and CT In vitro Nude mouse bearing DX-3 (human melanoma) xenograft tumor 18F-FDG ( + , 97%) IVIS 100 Li et al. 2010 [19] T Cerenkov Lu- minescence Tomography Multi-view tomography with a rotation stage obtained with a heterogeneous mouse model. Verified with SPECT In vitro Na131I source implanted in athymic nude mice Na131I ( -, 89.9%) IVIS Kinetic Hu et al. 2010 [20] Boschi and Spinelli Table (1) contd…. "
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    ABSTRACT: Cerenkov luminescence imaging (CLI) is a new technique that has rapidly gained great interest in the molecular imaging field bridging optical imaging and nuclear medicine. Based on the detection of Cerenkov radiation (CR) in biological tissue, in only five years many different applications of CLI were developed spanning from cancer imaging to Alzheimer’s disease and many different approaches were tested in order to increase its potentialities. In particular some efforts were made to transform CLI from a planar imaging technique into a tomographic technique or to shift the CR in a red-infrared radiation more suitable for biological applications. Moreover CLI, developed as a preclinical investigation, has obtained very quickly, interesting results on humans. Here we present a schematic and brief overview of the CLI landscape in order to show the principal results and applications to the biology. More precisely we focused on the potentialities of optical detection of radiotracers excluding the application of Cerenkov radiation obtained with the use of external radiation beam.
    01/2014; 3(2):106-117. DOI:10.2174/2211555203666141128002406
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