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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    • "Although it has been 80 years since its first observation [1], surprisingly little attention was given to the importance of the quantum nature of the charged particles producing the radiation. Since its discovery, the Čerenkov effect has become a fundamental part of many fields [2]: Devices like the ring-imaging Čerenkov detector are used for cosmic radiation measurements [3,4] , while other implications also suggest novel acceleration methods [5], and even an unusual imaging tool in biology [6,7]. Because of the fundamental nature of ČR, it is found in many different physical systems, such as in nonlinear optics891011, it is used in the design of quantum cascade lasers [12], and it is predicted to yield the generation of entangled photon pairs [13,14]. "
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    ABSTRACT: We show that the well-known Čerenkov effect contains new phenomena arising from the quantum nature of charged particles. The Čerenkov transition amplitudes allow coupling between the charged particle and the emitted photon through their orbital angular momentum and spin, by scattering into preferred angles and polarizations. Importantly, the spectral response reveals a discontinuity immediately below a frequency cutoff that can occur in the optical region. Near this cutoff, the intensity of the conventional Čerenkov radiation (ČR) is very small but still finite, while our quantum calculation predicts exactly zero intensity above the cutoff. Below that cutoff, with proper shaping of electron beams (ebeams), we predict that the traditional ČR angle splits into two distinctive cones of photonic shockwaves. One of the shockwaves can move along a backward cone, otherwise considered impossible for conventional ČR in ordinary matter. Our findings are observable for ebeams with realistic parameters, offering new applications including novel quantum optics sources, and opening a new realm for Čerenkov detectors involving the spin and orbital angular momentum of charged particles.
    Full-text · Article · Oct 2015 · Physical Review X
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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.
    Full-text · Article · Aug 2015 · Journal of Fluorine Chemistry
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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.
    Full-text · Article · Aug 2014 · Theranostics
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