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1.  In vivo Cerenkov luminescence imaging: a new tool for molecular imaging 
Cerenkov radiation is a phenomenon where optical photons are emitted when a charged particle moves faster than the speed of light for the medium in which it travels. Recently, we and others have discovered that measurable visible light due to the Cerenkov effect is produced in vivo following the administration of β-emitting radionuclides to small animals. Furthermore, the amounts of injected activity required to produce a detectable signal are consistent with small-animal molecular imaging applications. This surprising observation has led to the development of a new hybrid molecular imaging modality known as Cerenkov luminescence imaging (CLI), which allows the spatial distribution of biomolecules labelled with β-emitting radionuclides to be imaged in vivo using sensitive charge-coupled device cameras. We review the physics of Cerenkov radiation as it relates to molecular imaging, present simulation results for light intensity and spatial distribution, and show an example of CLI in a mouse cancer model. CLI allows many common radiotracers to be imaged in widely available in vivo optical imaging systems, and, more importantly, provides a pathway for directly imaging β−-emitting radionuclides that are being developed for therapeutic applications in cancer and that are not readily imaged by existing methods.
doi:10.1098/rsta.2011.0271
PMCID: PMC3263789  PMID: 22006909
Cerenkov radiation; optical imaging; molecular imaging
2.  Cerenkov Luminescence Tomography for Small Animal Imaging 
Optics letters  2010;35(7):1109-1111.
Cerenkov radiation is a well-known phenomenon, in which optical photons are emitted by charged particles moving faster than the speed of light in a medium. We have observed Cerenkov photons emitted from beta-emitting radiotracers such as 18F-fluorodeoxyglucose using a sensitive CCD camera. Phantom and in vivo mouse imaging experiments have demonstrated that surface measurements of the emitted Cerenkov optical photons could be used to reconstruct the radiotracer activity distribution inside an object by modeling the optical photon propagation with the diffusion equation and reconstructing the optical emission source distribution iteratively with a preconditioned conjugate gradient method (PCG). This is analogous to methods used for bioluminescence tomography. We refer to this as Cerenkov luminescence tomography (CLT), allowing the biodistribution of diagnostic and therapeutic beta-emitting radiolabeled agents to be imaged by detection and reconstruction of the optical Cerenkov signal.
PMCID: PMC2852688  PMID: 20364233
3.  Intraoperative Imaging of Positron Emission Tomographic Radiotracers Using Cerenkov Luminescence Emissions 
Molecular imaging  2011;10(3):177-186.
Imaging the location and extent of cancer provides invaluable information before, during, and after surgery. The majority of “image-guided” methods that use, for example, positron emission tomography (PET) involve preoperative imaging and do not provide real-time information during surgery. It is now well established that the inherent optical emissions (Cerenkov radiation) from various β-emitting radionuclides can be visualized by Cerenkov luminescence imaging (CLI). Here we report the full characterization of CLI using the positron-emitting radiotracer 89Zr-DFO-trastuzumab for target-specific, quantitative imaging of HER2/neu-positive tumors in vivo. We also provide the first demonstration of the feasibility of using CLI for true image-guided, intraoperative surgical resection of tumors. Analysis of optical CLIs provided accurate, quantitative information on radiotracer biodistribution and tissue uptake that correlated well with the concordant PET images. CLI, PET, and biodistribution studies revealed target-specific uptake of 89Zr-DFO-trastuzumab in BT-474 (HER2/neu positive) versus MDA-MB-468 (HER2/neu negative) xenografts in the same mice. Competitive inhibition (blocking) studies followed by CLI also confirmed the in vivo immunoreactivity and specificity of 89Zr-DFO-trastuzumab for HER2/neu. Overall, these results strongly support the continued development of CLI as a preclinical and possible clinical tool for use in molecular imaging and surgical procedures for accurately defining tumor margins.
PMCID: PMC3083828  PMID: 21496448
4.  Cerenkov Luminescence Tomography for In Vivo Radiopharmaceutical Imaging 
Cerenkov luminescence imaging (CLI) is a cost-effective molecular imaging tool for biomedical applications of radiotracers. The introduction of Cerenkov luminescence tomography (CLT) relative to planar CLI can be compared to the development of X-ray CT based on radiography. With CLT, quantitative and localized analysis of a radiopharmaceutical distribution becomes feasible. In this contribution, a feasibility study of in vivo radiopharmaceutical imaging in heterogeneous medium is presented. Coupled with a multimodal in vivo imaging system, this CLT reconstruction method allows precise anatomical registration of the positron probe in heterogeneous tissues and facilitates the more widespread application of radiotracers. Source distribution inside the small animal is obtained from CLT reconstruction. The experimental results demonstrated that CLT can be employed as an available in vivo tomographic imaging of charged particle emitters in a heterogeneous medium.
doi:10.1155/2011/641618
PMCID: PMC3124671  PMID: 21747821
5.  Enhancement of Cerenkov Luminescence Imaging by Dual Excitation of Er3+, Yb3+-Doped Rare-Earth Microparticles 
PLoS ONE  2013;8(10):e77926.
Cerenkov luminescence imaging (CLI) has been successfully utilized in various fields of preclinical studies; however, CLI is challenging due to its weak luminescent intensity and insufficient penetration capability. Here, we report the design and synthesis of a type of rare-earth microparticles (REMPs), which can be dually excited by Cerenkov luminescence (CL) resulting from the decay of radionuclides to enhance CLI in terms of intensity and penetration. Methods: Yb3+- and Er3+- codoped hexagonal NaYF4 hollow microtubes were synthesized via a hydrothermal route. The phase, morphology, and emission spectrum were confirmed for these REMPs by power X-ray diffraction (XRD), scanning electron microscopy (SEM), and spectrophotometry, respectively. A commercial CCD camera equipped with a series of optical filters was employed to quantify the intensity and spectrum of CLI from radionuclides. The enhancement of penetration was investigated by imaging studies of nylon phantoms and nude mouse pseudotumor models. Results: the REMPs could be dually excited by CL at the wavelengths of 520 and 980 nm, and the emission peaks overlaid at 660 nm. This strategy approximately doubled the overall detectable intensity of CLI and extended its maximum penetration in nylon phantoms from 5 to 15 mm. The penetration study in living animals yielded similar results. Conclusions: this study demonstrated that CL can dually excite REMPs and that the overlaid emissions in the range of 660 nm could significantly enhance the penetration and intensity of CL. The proposed enhanced CLI strategy may have promising applications in the future.
doi:10.1371/journal.pone.0077926
PMCID: PMC3808356  PMID: 24205030
6.  Cerenkov Radiation Energy Transfer (CRET) Imaging: A Novel Method for Optical Imaging of PET Isotopes in Biological Systems 
PLoS ONE  2010;5(10):e13300.
Background
Positron emission tomography (PET) allows sensitive, non-invasive analysis of the distribution of radiopharmaceutical tracers labeled with positron (β+)-emitting radionuclides in small animals and humans. Upon β+ decay, the initial velocity of high-energy β+ particles can momentarily exceed the speed of light in tissue, producing Cerenkov radiation that is detectable by optical imaging, but is highly absorbed in living organisms.
Principal Findings
To improve optical imaging of Cerenkov radiation in biological systems, we demonstrate that Cerenkov radiation from decay of the PET isotopes 64Cu and 18F can be spectrally coupled by energy transfer to high Stokes-shift quantum nanoparticles (Qtracker705) to produce highly red-shifted photonic emissions. Efficient energy transfer was not detected with 99mTc, a predominantly γ-emitting isotope. Similar to bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), herein we define the Cerenkov radiation energy transfer (CRET) ratio as the normalized quotient of light detected within a spectral window centered on the fluorophore emission divided by light detected within a spectral window of the Cerenkov radiation emission to quantify imaging signals. Optical images of solutions containing Qtracker705 nanoparticles and [18F]FDG showed CRET ratios in vitro as high as 8.8±1.1, while images of mice with subcutaneous pseudotumors impregnated with Qtracker705 following intravenous injection of [18F]FDG showed CRET ratios in vivo as high as 3.5±0.3.
Conclusions
Quantitative CRET imaging may afford a variety of novel optical imaging applications and activation strategies for PET radiopharmaceuticals and other isotopes in biomaterials, tissues and live animals.
doi:10.1371/journal.pone.0013300
PMCID: PMC2952622  PMID: 20949021
7.  Cerenkov luminescence imaging of medical isotopes 
The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies.
Methods
In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters 18F, 64Cu, 89Zr, and 124I; β-emitter 131I; and α-particle emitter 225Ac for potential use in CLI. The novel radiolabeled monoclonal antibody 89Zr-desferrioxamine B-[DFO-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies.
Results
Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-,β-, and α-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of 89Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities.
Conclusion
These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or γ-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals
doi:10.2967/jnumed.110.076521
PMCID: PMC3068779  PMID: 20554722
Imaging technology; Cerenkov; PET; optical imaging; 89Zr; 124I; 131I; 64Cu; 225Ac; 18F; radioimmunoconjugate; prostate-specific membrane antigen (PSMA); J591; monoclonal antibodies
8.  Endoscopic imaging of Cerenkov luminescence 
Biomedical Optics Express  2012;3(6):1215-1225.
We demonstrate feasibility of endoscopic imaging of Cerenkov light originated when charged nuclear particles, emitted from radionuclides, travel through a biological tissue of living subjects at superluminal velocity. The endoscopy imaging system consists of conventional optical fiber bundle/ clinical endoscopes, an optical imaging lens system, and a sensitive low-noise charge coupled device (CCD) camera. Our systematic studies using phantom samples show that Cerenkov light from as low as 1 µCi of radioactivity emitted from 18F-Fluorodeoxyglucose (FDG) can be coupled and transmitted through conventional optical fibers and endoscopes. In vivo imaging experiments with tumor bearing mice, intravenously administered with 18F-FDG, further demonstrated that Cerenkov luminescence endoscopy is a promising new tool in the field of endoscopic molecular imaging.
doi:10.1364/BOE.3.001215
PMCID: PMC3370963  PMID: 22741069
(170.2150) Endoscopic imaging; (170.0110) Imaging systems; (170.4580) Optical diagnostics for medicine
9.  Optical imaging of Cerenkov light generation from positron-emitting radiotracers 
Physics in medicine and biology  2009;54(16):N355-N365.
Radiotracers labeled with high-energy positron-emitters, such as those commonly used for positron emission tomography (PET) studies, emit visible light immediately following decay in a medium. This phenomenon, not previously described for these imaging tracers, is consistent with Cerenkov radiation and has several potential applications, especially for in vivo molecular imaging studies. Herein we detail a new molecular imaging tool, Cerenkov Luminescence Imaging, the experiments conducted that support our interpretation of the source of the signal, and proof-of-concept in vivo studies that set the foundation for future application of this new method.
doi:10.1088/0031-9155/54/16/N01
PMCID: PMC2765256  PMID: 19636082
10.  Radioluminescent Gold Nanocages with Controlled Radioactivity for Real-time In Vivo Imaging 
Nano letters  2013;13(2):581-585.
Cerenkov luminescence imaging based on light emission from the decay of radionuclides has recently drawn great interest in molecular imaging. In this paper, we report, for the first time, the Cerenkov luminescence phenomenon of 198Au isotope, as well as a facile route to the preparation of radioluminescent Au nanocages without additional radiolabeling or dye conjugation. The specific radioactivity of the Au nanocages could be easily and precisely controlled by varying the concentration of H198AuCl4 precursor used for the galvanic replacement reaction. The direct incorporation of 198Au atoms into the structure of Au nanocages enabled the ability of accurate analysis and real-time imaging in vivo. Furthermore, under biological conditions, the radioactive Au nanocages were shown to emit light with wavelengths in the visible and near-infrared regions, enabling luminescence imaging of the whole mice in vivo, as well as the organs ex vivo. When combined with their favorable scattering and absorption properties in the near-infrared region, the radioactive Au nanocages can serve as a new platform for multimodality imaging and will have a significant impact on both small animal and clinical imaging.
doi:10.1021/nl304111v
PMCID: PMC3576732  PMID: 23360442
Gold nanocages; cancer imaging; Cerenkov luminescence imaging; radioactive
11.  Quantitative imaging of disease signatures through radioactive decay signal conversion 
Nature medicine  2013;19(10):1345-1350.
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, but radioactive decay is a physical constant and signal is independent of biological interactions. Here we introduce a framework of novel targeted and activatable probes excited by a nuclear decay-derived signal to identify and measure molecular signatures of disease. This was accomplished utilizing Cerenkov luminescence (CL), the light produced by β-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 information from a PET scan, we demonstrate novel medical utility by quantitatively determining prognostically relevant enzymatic activity. This technique can be applied to monitor other markers and facilitates a shift towards activatable nuclear medicine agents.
doi:10.1038/nm.3323
PMCID: PMC3795968  PMID: 24013701
Activatable probes; Molecular imaging; Nanoparticles; Cerenkov luminescence
12.  Clinical Cerenkov Luminescence Imaging of 18F-FDG 
The aim of this study was to determine the feasibility of Cerenkov luminescence (CL) imaging of patients undergoing diagnostic 18F-FDG scans to detect nodal disease.
Methods
Patients undergoing routine 18F-FDG PET/CT for various malignancies consented to being scanned for CL. White-light and Cerenkov images (5-min acquisition) of the surface of the patient contralateral to and at the site of nodal 18F-FDG uptake were acquired using a cooled, intensified charge-coupled-device camera.
Results
The camera demonstrated linear correlation between activity and counts into the low nanocurie range using 18F-FDG. Imaging of patients revealed the presence of 18F-FDG uptake in nodes that demonstrated uptake on PET. A correlation between maximum standardized uptake value from PET and counting rate per area on the CL imaging was established.
Conclusion
CL imaging with diagnostic doses of 18F-FDG is feasible and can aid in detecting disease in the clinical setting.
doi:10.2967/jnumed.113.127266
PMCID: PMC3903390  PMID: 24078721
Cerenkov luminescence imaging; 18F-FDG; PET/CT; clinical
13.  On the potential for molecular imaging with Cerenkov luminescence 
Optics letters  2010;35(23):3889-3891.
Recent observation of optical luminescence due to beta decay from suitable radiotracers has led to the possible development of new preclinical optical imaging methods. The generation of photons that can be detected using instrumentation optimized for bioluminescence imaging has been putatively associated with the Cerenkov effect. We describe the simultaneous utilization of fluorescence reporters to convert the Cerenkov luminescence to longer wavelengths for better tissue penetration and also for modulating the luminescence spectrum for potential molecular imaging strategies.
PMCID: PMC3023798  PMID: 21124555
14.  In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18F-FDG via Cerenkov Luminescence Imaging 
PLoS ONE  2013;8(4):e62007.
Objective
Brown adipose tissue (BAT), a specialized tissue for thermogenesis, plays important roles for metabolism and energy expenditure. Recent studies validated BAT’s presence in human adults, making it an important re-emerging target for various pathologies. During this validation, PET images with 18F-FDG showed significant uptake of 18F-FDG by BAT under certain conditions. Here, we demonstrated that Cerenkov luminescence imaging (CLI) using 18F-FDG could be utilized for in vivo optical imaging of BAT in mice.
Methods
Mice were injected with 18F-FDG and imaged 60 minutes later with open filter and 2 minute acquisition. In vivo activation of BAT was performed by norepinephrine and cold treatment under isoflurane or ketamine anesthesia. Spectral unmixing and 3D imaging reconstruction were conducted with multiple-filter CLI images.
Results
1) It was feasible to use CLI with 18F-FDG to image interscapular BAT in mice, with the majority of the signal (>85%) at the interscapular site originating from BAT; 2) The method was reliable because excellent correlations between in vivo CLI, ex vivo CLI, and ex vivo radioactivity were observed; 3) CLI could be used for monitoring BAT activation under different conditions; 4) CLI signals from the group under short-term isoflurane anesthesia were significantly higher than that from the group under long-term anesthesia; 5) The CLI spectrum of 18F-FDG with a peak at 640 nm in BAT after spectral unmixing reflected the actual context of BAT; 6) Finally 3D reconstruction images showed excellent correlation between the source of the light signal and the location and physical shape of BAT.
Conclusion
CLI with 18F-FDG is a feasible and reliable method for imaging BAT in mice. Compared to PET imaging, CLI is significantly cheaper, faster for 2D planar imaging and easier to use. We believe that this method could be used as an important tool for researchers investigating BAT.
doi:10.1371/journal.pone.0062007
PMCID: PMC3634850  PMID: 23637947
15.  Quantitative Modeling of Cerenkov Light Production Efficiency from Medical Radionuclides 
PLoS ONE  2012;7(2):e31402.
There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use.
doi:10.1371/journal.pone.0031402
PMCID: PMC3282695  PMID: 22363636
16.  Three-dimensional Noninvasive Monitoring Iodine-131 Uptake in the Thyroid Using a Modified Cerenkov Luminescence Tomography Approach 
PLoS ONE  2012;7(5):e37623.
Background
Cerenkov luminescence tomography (CLT) provides the three-dimensional (3D) radiopharmaceutical biodistribution in small living animals, which is vital to biomedical imaging. However, existing single-spectral and multispectral methods are not very efficient and effective at reconstructing the distribution of the radionuclide tracer. In this paper, we present a semi-quantitative Cerenkov radiation spectral characteristic-based source reconstruction method named the hybrid spectral CLT, to efficiently reconstruct the radionuclide tracer with both encouraging reconstruction results and less acquisition and image reconstruction time.
Methodology/Principal Findings
We constructed the implantation mouse model implanted with a 400 µCi Na131I radioactive source and the physiological mouse model received an intravenous tail injection of 400 µCi radiopharmaceutical Iodine-131 (I-131) to validate the performance of the hybrid spectral CLT and compared the reconstruction results, acquisition, and image reconstruction time with that of single-spectral and multispectral CLT. Furthermore, we performed 3D noninvasive monitoring of I-131 uptake in the thyroid and quantified I-131 uptake in vivo using hybrid spectral CLT. Results showed that the reconstruction based on the hybrid spectral CLT was more accurate in localization and quantification than using single-spectral CLT, and was more efficient in the in vivo experiment compared with multispectral CLT. Additionally, 3D visualization of longitudinal observations suggested that the reconstructed energy of I-131 uptake in the thyroid increased with acquisition time and there was a robust correlation between the reconstructed energy versus the gamma ray counts of I-131 (). The ex vivo biodistribution experiment further confirmed the I-131 uptake in the thyroid for hybrid spectral CLT.
Conclusions/Significance
Results indicated that hybrid spectral CLT could be potentially used for thyroid imaging to evaluate its function and monitor its treatment for thyroid cancer.
doi:10.1371/journal.pone.0037623
PMCID: PMC3358266  PMID: 22629431
17.  New covalent capture probes for imaging and therapy, based on a combination of binding affinity and disulfide bond formation 
Bioconjugate chemistry  2011;22(8):1479-1483.
We describe the synthesis and development of new reactive DOTA-metal complexes for covalently targeting engineered receptors in vivo, which have superior tumor uptake and clearance properties for biomedical applications. These probes are found to clear efficiently through the kidneys and minimally through other routes, but bind persistently in the tumor target. We also explore the new technique of Cerenkov luminescence imaging to optically monitor radiolabeled probe distribution and kinetics in vivo. Cerenkov luminescence imaging uniquely enables sensitive noninvasive in vivo imaging of a β− emitter such as 90Y with an optical imager.
doi:10.1021/bc2002049
PMCID: PMC3158659  PMID: 21755984
18.  Three-dimensional Čerenkov tomography of energy deposition from ionizing radiation beams 
Optics letters  2013;38(5):634-636.
Since its discovery during the 1930’s, the Čerenkov effect (light emission from charged particles traveling faster than the local speed of light in a dielectric medium) has been paramount in the development of high-energy physics research. The ability of the emitted light to describe a charged particle’s trajectory, energy, velocity, and mass has allowed scientists to study subatomic particles, detect neutrinos, and explore the properties of interstellar matter. However, all applications of the process to date have focused on identification of particle’s themselves, rather than their effect upon the surroundings through which they travel. Here, we explore a novel application of the Čerenkov effect for the recovery of the spatial distribution of ionizing radiation energy deposition in a medium, and apply it to the issue of dose determination in medical physics. By capturing multiple projection images of the Čerenkov light induced by a medical linear accelerator (LINAC) x-ray photon beam, we demonstrate the successful three-dimensional (3D) tomographic reconstruction of the imparted dose distribution for the first time.
PMCID: PMC3698946  PMID: 23455248
19.  Use of a highly sensitive two-dimensional luminescence imaging system to monitor endogenous bioluminescence in plant leaves 
BMC Plant Biology  2004;4:19.
Background
All living organisms emit spontaneous low-level bioluminescence, which can be increased in response to stress. Methods for imaging this ultra-weak luminescence have previously been limited by the sensitivity of the detection systems used.
Results
We developed a novel configuration of a cooled charge-coupled device (CCD) for 2-dimensional imaging of light emission from biological material. In this study, we imaged photon emission from plant leaves. The equipment allowed short integration times for image acquisition, providing high resolution spatial and temporal information on bioluminescence. We were able to carry out time course imaging of both delayed chlorophyll fluorescence from whole leaves, and of low level wound-induced luminescence that we showed to be localised to sites of tissue damage. We found that wound-induced luminescence was chlorophyll-dependent and was enhanced at higher temperatures.
Conclusions
The data gathered on plant bioluminescence illustrate that the equipment described here represents an improvement in 2-dimensional luminescence imaging technology. Using this system, we identify chlorophyll as the origin of wound-induced luminescence from leaves.
doi:10.1186/1471-2229-4-19
PMCID: PMC535552  PMID: 15550176
20.  A practical guide to the construction of radiometallated bioconjugates for positron emission tomography 
Positron emission tomography (PET) has become a vital imaging modality in the diagnosis and treatment of disease, most notably cancer. A wide array of small molecule PET radiotracers have been developed that employ the short half-life radionuclides 11C, 13N, 15O, and 18F. However, PET radiopharmaceuticals based on biomolecular targeting vectors have been the subject of dramatically increased research in both the laboratory and the clinic. Typically based on antibodies, oligopeptides, or oligonucleotides, these tracers have longer biological half-lives than their small molecule counterparts and thus require labeling with radionuclides with longer, complementary radioactive half-lives, such as the metallic isotopes 64Cu, 68Ga, 86Y, and 89Zr. Each bioconjugate radiopharmaceutical has four component parts: biomolecular vector, radiometal, chelator, and covalent link between chelator and biomolecule. With the exception of the radiometal, a tremendous variety of choices exists for each of these pieces, and a plethora of different chelation, conjugation, and radiometallation strategies have been utilized to create agents ranging from 68Ga-labeled pentapeptides to 89Zr-labeled monoclonal antibodies. Herein, the authors present a practical guide to the construction of radiometal-based PET bioconjugates, in which the design choices and synthetic details of a wide range of biomolecular tracers from the literature are collected in a single reference. In assembling this information, the authors hope both to illuminate the diverse methods employed in the synthesis of these agents and also to create a useful reference for molecular imaging researchers both experienced and new to the field.
doi:10.1039/c0dt01595d
PMCID: PMC3773488  PMID: 21442098
21.  Time-gated Cerenkov emission spectroscopy from linear accelerator irradiation of tissue phantoms 
Optics letters  2012;37(7):1193-1195.
Radiation from a linear accelerator induces Cerenkov emission in tissue, which has recently been shown to produce biochemical spectral signatures which can be interpreted to estimate tissue hemoglobin and oxygen saturation or molecular fluorescence from reporters. The Cerenkov optical light levels are in the range of 10−6–10−9 W/cm2, which limits the practical utility of the signal in routine radiation therapy monitoring. However due to the fact that the radiation is pulsed, gated-acquisition of the signal allows detection in the presence of ambient lighting, as is demonstrated here. This observation has the potential to significantly increase the value of Cerenkov emission spectroscopy during radiation therapy to monitor tissue molecular events.
PMCID: PMC3698962  PMID: 22466192
22.  Functional Imaging for Prostate Cancer: Therapeutic Implications 
Seminars in nuclear medicine  2012;42(5):328-342.
Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities CT or MRI (SPECT/CT, PET/CT, and PET/MRI) are promising tools for the management of prostate cancer particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection, to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regards to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, while the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects.
doi:10.1053/j.semnuclmed.2012.04.004
PMCID: PMC3408625  PMID: 22840598
23.  On the nature of the light produced within PMMA optical light guides in scintillation fiber-optic dosimetry 
Physics in medicine and biology  2013;58(7):2073-2084.
The goal of this study was to evaluate the nature of the stem effect light produced within an optical fiber, to quantify its composition, and to evaluate the efficiency of the chromatic technique to remove the stem effect. Spectrometry studies were performed during irradiations of a bare PMMA optical fiber with kilovoltage x-rays from a superficial therapy unit, an Ir-192 high-dose-rate brachytherapy source, a Co-60 external-therapy unit, and megavoltage electrons and x-rays from a linear accelerator. Stem effect spectra can be accurately modeled by a linear combination of the Cerenkov light and fluorescence emitted spectra. Fluorescence light contributes more for lower-energy modalities. Cerenkov light contributes more as the energy increases above the threshold for its production. The chromatic stem effect removal technique is accurate in most of the situations. However, noticeable differences were obtained between very specific high-energy irradiation conditions. It would be advantageous to implement an additional channel in the chromatic stem effect removal chain or implement a spectral approach to independently remove the Cerenkov and the fluorescence components from the signal of interest. This would increase the accuracy and versatility of the actual chromatic stem effect removal technique.
doi:10.1088/0031-9155/58/7/2073
PMCID: PMC3777626  PMID: 23470253
fluorescence; Cerenkov; scintillation; fiber; stem effect
24.  Luminescent proteins for high-speed single-cell and whole-body imaging 
Nature Communications  2012;3:1262-.
The use of fluorescent proteins has revolutionized our understanding of biological processes. However, the requirement for external illumination precludes their universal application to the study of biological processes in all tissues. Although light can be created by chemiluminescence, light emission from existing chemiluminescent probes is too weak to use this imaging modality in situations when fluorescence cannot be used. Here we report the development of the brightest luminescent protein to date, Nano-lantern, which is a chimera of enhanced Renilla luciferase and Venus, a fluorescent protein with high bioluminescence resonance energy transfer efficiency. Nano-lantern allows real-time imaging of intracellular structures in living cells with spatial resolution equivalent to fluorescence and sensitive tumour detection in freely moving unshaved mice. We also create functional indicators based on Nano-lantern that can image Ca2+, cyclic adenosine monophosphate and adenosine 5′-triphosphate dynamics in environments where the use of fluorescent indicators is not feasible. These luminescent proteins allow visualization of biological phenomena at previously unseen single-cell, organ and whole-body level in animals and plants.
Luminescent proteins are important tools for biomedical imaging but tend to emit fairly little light. Saito et al.. describe a brighter version of a bioluminescent protein that can visualize intracellular dynamics of various signalling molecules with high spatial and temporal resolution.
doi:10.1038/ncomms2248
PMCID: PMC3535334  PMID: 23232392
25.  Cerenkov radiation imaging as a method for quantitative measurements of beta particles in a microfluidic chip 
Physics in medicine and biology  2009;54(22):6757-6771.
It has been observed that microfluidic chips used for synthesizing 18F-labeled compounds demonstrate visible light emission without nearby scintillators or fluorescent materials. The origin of the light was investigated and found to be consistent with the emission characteristics from Cerenkov radiation. Since 18F decays through the emission of high-energy positrons, the energy threshold for beta particles, i.e., electrons or positrons, to generate Cerenkov radiation was calculated for water and polydimethylsiloxane (PDMS), the most commonly used polymer-based material for microfluidic chips. Beta particles emitted from 18F have a continuous energy spectrum, with a maximum energy that exceeds this energy threshold for both water and PDMS. In addition, the spectral characteristics of the emitted light from 18F in distilled water were also measured, yielding a broad distribution from 300 nm to 700 nm, with higher intensity at shorter wavelengths. A photograph of the 18F solution showed a bluish-white light emitted from the solution, further suggesting Cerenkov radiation.
In this study, the feasibility of using this Cerenkov light emission as a method for quantitative measurements of the radioactivity within the microfluidic chip in situ was evaluated. A detector previously developed for imaging microfluidic platforms was used. The detector consisted of a charge coupled device (CCD) optically coupled to a lens. The system spatial resolution, minimum detectable activity and dynamic range were evaluated. In addition, a calibration of Cerenkov signal versus activity concentration in the microfluidic chip was determined. This novel method of Cerenkov radiation measurements will provide researchers with a simple yet robust quantitative imaging tool for microfluidic applications utilizing beta particles.
doi:10.1088/0031-9155/54/22/001
PMCID: PMC2794558  PMID: 19847018

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