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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 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
3.  Cerenkov Imaging 
Advances in cancer research  2014;124:213-234.
Cerenkov luminescence (CL) has been used recently in a plethora of medical applications like imaging and therapy with clinically relevant medical isotopes. The range of medical isotopes used is fairly large and expanding. The generation of in vivo light is useful since it circumvents depth limitations for excitation light. Cerenkov luminescence imaging (CLI) is much cheaper in terms of infrastructure than positron emission tomography (PET) and is particularly useful for imaging of superficial structures. Imaging can basically be done using a sensitive camera optimized for low-light conditions, and it has a better resolution than any other nuclear imaging modality. CLI has been shown to effectively diagnose disease with regularly used PET isotope (18F-FDG) in clinical setting. Cerenkov luminescence tomography, Cerenkov luminescence endoscopy, and intraoperative Cerenkov imaging have also been explored with positive conclusions expanding the current range of applications. Cerenkov has also been used to improve PET imaging resolution since the source of both is the radioisotope being used. Smart imaging agents have been designed based on modulation of the Cerenkov signal using small molecules and nanoparticles giving better insight of the tumor biology.
doi:10.1016/B978-0-12-411638-2.00006-9
PMCID: PMC4329979  PMID: 25287690
4.  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
5.  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
6.  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
7.  Proof-of-Concept Study of Monitoring Cancer Drug Therapy with Cerenkov Luminescence Imaging 
Cerenkov luminescence imaging (CLI) has emerged as a less expensive, easier-to-use, and higher-throughput alternative to other nuclear imaging modalities such as PET. It is expected that CLI will find many applications in biomedical research such as cancer detection, probe development, drug screening, and therapy monitoring. In this study, we explored the possibility of using CLI to monitor drug efficacy by comparisons against PET. To assess the performance of both modalities in therapy monitoring, 2 murine tumor models (large cell lung cancer cell line H460 and prostate cancer cell line PC3) were given bevacizumab versus vehicle treatments. Two common radiotracers, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and 18F-FDG, were used to monitor bevacizumab treatment efficacy.
Methods
One group of mice (n = 6) was implanted with H460 xenografts bilaterally in the shoulder region, divided into treatment and control groups (n = 3 each), injected with 18F-FLT, and imaged with PET immediately followed by CLI. The other group of mice (n = 6) was implanted with PC3 xenografts in the same locations, divided into treatment and control groups (n = 3 each), injected with 18F-FDG, and imaged by the same modalities. Bevacizumab treatment was performed by 2 injections of 20 mg/kg at days 0 and 2.
Results
On 18F-FLT scans, both CLI and PET revealed significantly decreased signals from H460 xenografts in treated mice from pretreatment to day 3. Moderately increased to unchanged signals were observed in untreated mice. On 18F-FDG scans, both CLI and PET showed relatively unchanged signals from PC3 tumors in both treated and control groups. Quantifications of tumor signals of Cerenkov luminescence and PET images showed that the 2 modalities had excellent correlations (R2 > 0.88 across all study groups).
Conclusion
CLI and PET exhibit excellent correlations across different tumor xenografts and radiotracers. This is the first study, to our knowledge, demonstrating the use of CLI for monitoring cancer treatment. The findings warrant further exploration and optimization of CLI as an alternative to PET in preclinical therapeutic monitoring and drug screening.
doi:10.2967/jnumed.111.094623
PMCID: PMC4143153  PMID: 22241909
therapy monitoring; Cerenkov luminescence imaging; radionuclides; optical imaging; PET; Avastin
8.  Positron Lymphography: Multimodal, High-Resolution, Dynamic Mapping and Resection of Lymph Nodes After Intradermal Injection of 18F-FDG 
The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of 99mTc-sulfur colloid (99mTc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media (99mTc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of 18F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from 18F-FDG was evaluated to optically guide surgical resection of LNs.
Methods
Imaging of 18F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of 18F-FDG and was compared with that of 99mTc-SC. Verification of uptake and the ability to use 18F-FDG CR to guide nodal removal were confirmed histologically.
Results
Intradermal injection of 18F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. 18F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection.
Conclusion
Intradermal 18F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).
doi:10.2967/jnumed.112.104349
PMCID: PMC3537831  PMID: 22872741
lymph node mapping; PET/CT; Cerenkov; intraoperative
9.  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
10.  Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga]gallium chloride 
EJNMMI Research  2014;4:15.
Background
Cerenkov luminescence imaging (CLI) is an emerging imaging technique where visible light emitted from injected beta-emitting radionuclides is detected with an optical imaging device. CLI research has mostly been focused on positive contrast imaging for ascertaining the distribution of the radiotracer in a way similar to other nuclear medicine techniques. Rather than using the conventional technique of measuring radiotracer distribution, we present a new approach of negative contrast imaging, where blood vessel attenuation of Cerenkov light emitted by [68Ga]GaCl3 is used to image vasculature.
Methods
BALB/c nude mice were injected subcutaneously in the right flank with HT-1080 fibrosarcoma cells 14 to 21 days prior to imaging. On the imaging day, [68Ga]GaCl3 was injected and the mice were imaged from 45 to 90 min after injection using an IVIS Spectrum in vivo imaging system. The mice were imaged one at a time, and manual focus was used to bring the skin into focus. The smallest view with pixel size around 83 μm was used to achieve a sufficiently high image resolution for blood vessel imaging.
Results
The blood vessels in the tumor were clearly visible, attenuating 7% to 18% of the light. Non-tumor side blood vessels had significantly reduced attenuation of 2% to 4%. The difference between the attenuation of light of tumor vessels (10% ± 4%) and the non-tumor vessels (3% ± 1%) was significant. Moreover, a necrotic core confirmed by histology was clearly visible in one of the tumors with a 21% reduction in radiance.
Conclusions
The negative contrast CLI technique is capable of imaging vasculature using [68Ga]GaCl3. Since blood vessels smaller than 50 μm in diameter could be imaged, CLI is able to image structures that conventional nuclear medicine techniques cannot. Thus, the negative contrast imaging technique shows the feasibility of using CLI to perform angiography on superficial blood vessels, demonstrating an advantage over conventional nuclear medicine techniques.
doi:10.1186/2191-219X-4-15
PMCID: PMC3974015  PMID: 24606872
Cerenkov luminescence imaging; [68Ga]gallium chloride; Tumor; Blood vessels; Negative contrast imaging
11.  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
12.  Optimization of microfluidic PET tracer synthesis with Cerenkov imaging† 
The Analyst  2013;138(19):5654-5664.
Microfluidic technologies provide an attractive platform for the synthesis of radiolabeled compounds. Visualization of radioisotopes on chip is critical for synthesis optimization and technological development. With Cerenkov imaging, beta particle emitting isotopes can be localized with a sensitive CCD camera. In order for Cerenkov imaging to also serve as a quantitative tool, it is necessary to understand how material properties relevant to Cerenkov emission, namely, index of refraction and beta particle stopping power, affect Cerenkov light output. In this report, we investigate the fundamental physical characteristics of Cerenkov photon yield at different stages of [18F]FDG synthesis on the electrowetting on dielectric (EWOD) microfluidic platform. We also demonstrate how Cerenkov imaging has enabled synthesis optimization. Geant4, a Monte Carlo program applied extensively in high energy physics, is used to simulate Cerenkov photon yield from 18F beta particles traversing materials of interest during [18F]FDG synthesis on chip. Our simulations show that the majority (approximately two-thirds) of the 18F beta particle energy available to produce Cerenkov photons is deposited on the glass plates of the EWOD chip. This result suggests the possibility of using a single calibration factor to convert Cerenkov signal to radioactivity, independent of droplet composition. We validate our simulations with a controlled measurement examining varying ratios of [18O]H2O, dimethyl sulfoxide (DMSO), and acetonitrile (MeCN), and find a consistent calibration independent of solvent composition. However, the calibration factor may underestimate the radioactivity in actual synthesis due to discoloration of the droplet during certain steps of probe synthesis. In addition to the attractive quantitative potential of Cerenkov imaging, this imaging strategy provides indispensable qualitative data to guide synthesis optimization. We are able to use this imaging technique to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50±3% (n=3) to 72±13% (n=5).
doi:10.1039/c3an01113e
PMCID: PMC3812546  PMID: 23928799
13.  Performance evaluation of endoscopic Cerenkov luminescence imaging system: in vitro and pseudotumor studies 
Biomedical Optics Express  2014;5(10):3660-3670.
By integrating the clinically used endoscope with the emerging Cerenkov luminescence imaging (CLI) technology, a new endoscopic Cerenkov luminescence imaging (ECLI) system was developed. The aim is to demonstrate the potential of translating CLI to clinical studies of gastrointestinal (GI) tract diseases. We systematically evaluated the feasibility and performance of the developed ECLI system with a series of in vitro and pseudotumor experiments. The ECLI system is comprised of an electron multiplying charge coupled device (EMCCD) camera coupled with a clinically used endoscope via an optical adapter. A 1951-USAF test board was used to measure the white-light lateral resolution, while a homemade test chart filled with 68Ga was employed to measure the CL lateral resolution. Both in vitro and pseudotumor experiments were conducted to obtain the sensitivity of the ECLI system. The results were validated with that of CLI using EMCCD only, and the relative attenuation ratio of the ECLI system was calculated. Results showed that The white-light lateral resolution of the ECLI system was 198 µm, and the luminescent lateral resolution was better than 1 mm. Sensitivity experiments showed a theoretical sensitivity of 0.186 KBq/μl (5.033×10−3 μCi/μl) and 1.218 KBq/μl (32.922×10−3 μCi/μl) for the in vitro and pseudotumor studies, respectively. The relative attenuation ratio of ECLI to CLI was about 96%. The luminescent lateral resolution of the ECLI system was comparable with that of positron emission tomography (PET). The pseudotumor study illustrated the feasibility and applicability of the ECLI system in living organisms, indicating the potential for translating the CLI technology to the clinic.
doi:10.1364/BOE.5.003660
PMCID: PMC4206332  PMID: 25360380
(170.3660) Light propagation in tissues; (170.7050) Turbid media; (170.6935) Tissue characterization
14.  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
15.  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
16.  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
17.  Optimization of Multimodal Imaging of Mesenchymal Stem Cells Using the Human Sodium Iodide Symporter for PET and Cerenkov Luminescence Imaging 
PLoS ONE  2014;9(4):e94833.
Purpose
The use of stably integrated reporter gene imaging provides a manner to monitor the in vivo fate of engrafted cells over time in a non-invasive manner. Here, we optimized multimodal imaging (small-animal PET, Cerenkov luminescence imaging (CLI) and bioluminescence imaging (BLI)) of mesenchymal stem cells (MSCs), by means of the human sodium iodide symporter (hNIS) and firefly luciferase (Fluc) as reporters.
Methods
First, two multicistronic lentiviral vectors (LV) were generated for multimodal imaging: BLI, 124I PET/SPECT and CLI. Expression of the imaging reporter genes was validated in vitro using 99mTcO4− radioligand uptake experiments and BLI. Uptake kinetics, specificity and tracer elution were determined as well as the effect of the transduction process on the cell's differentiation capacity. MSCs expressing the LV were injected intravenously or subcutaneously and imaged using small-animal PET, CLI and BLI.
Results
The expression of both imaging reporter genes was functional and specific. An elution of 99mTcO4− from the cells was observed, with 31% retention after 3 h. After labeling cells with 124I in vitro, a significantly higher CLI signal was noted in hNIS expressing murine MSCs. Furthermore, it was possible to visualize cells injected intravenously using BLI or subcutaneously in mice, using 124I small-animal PET, CLI and BLI.
Conclusions
This study identifies hNIS as a suitable reporter gene for molecular imaging with PET and CLI, as confirmed with BLI through the expression of Fluc. It supports the potential for a wider application of hNIS reporter gene imaging and future clinical applications.
doi:10.1371/journal.pone.0094833
PMCID: PMC3991630  PMID: 24747914
18.  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
19.  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
20.  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
21.  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
22.  Measurement of Cerenkov Radiation Induced by the Gamma-Rays of Co-60 Therapy Units Using Wavelength Shifting Fiber 
Sensors (Basel, Switzerland)  2014;14(4):7013-7025.
In this study, a wavelength shifting fiber that shifts ultra-violet and blue light to green light was employed as a sensor probe of a fiber-optic Cerenkov radiation sensor. In order to characterize Cerenkov radiation generated in the developed wavelength shifting fiber and a plastic optical fiber, spectra and intensities of Cerenkov radiation were measured with a spectrometer. The spectral peaks of light outputs from the wavelength shifting fiber and the plastic optical fiber were measured at wavelengths of 500 and 510 nm, respectively, and the intensity of transmitted light output of the wavelength shifting fiber was 22.2 times higher than that of the plastic optical fiber. Also, electron fluxes and total energy depositions of gamma-ray beams generated from a Co-60 therapy unit were calculated according to water depths using the Monte Carlo N-particle transport code. The relationship between the fluxes of electrons over the Cerenkov threshold energy and the energy depositions of gamma-ray beams from the Co-60 unit is a near-identity function. Finally, percentage depth doses for the gamma-ray beams were obtained using the fiber-optic Cerenkov radiation sensor, and the results were compared with those obtained by an ionization chamber. The average dose difference between the results of the fiber-optic Cerenkov radiation sensor and those of the ionization chamber was about 2.09%.
doi:10.3390/s140407013
PMCID: PMC4029631  PMID: 24755521
Cerenkov radiation; wavelength shifting fiber; fiber-optic radiation sensor; radiation therapy
23.  Self-Illuminating 64Cu-Doped CdSe/ZnS Nanocrystals for in Vivo Tumor Imaging 
Construction of self-illuminating semiconducting nanocrystals, also called quantum dots (QDs), has attracted much attention recently due to their potential as highly sensitive optical probes for biological imaging applications. Here we prepared a self-illuminating QD system by doping positron-emitting radionuclide 64Cu into CdSe/ZnS core/shell QDs via a cation-exchange reaction. The 64Cu-doped CdSe/ZnS QDs exhibit efficient Cerenkov resonance energy transfer (CRET). The signal of 64Cu can accurately reflect the biodistribution of the QDs during circulation with no dissociation of 64Cu from the nanoparticles. We also explored this system for in vivo tumor imaging. This nanoprobe showed high tumor-targeting ability in a U87MG glioblastoma xenograft model (12.7% ID/g at 17 h time point) and feasibility for in vivo luminescence imaging of tumor in the absence of excitation light. The availability of these self-illuminating integrated QDs provides an accurate and convenient tool for in vivo tumor imaging and detection.
doi:10.1021/ja410438n
PMCID: PMC4004262  PMID: 24401138
24.  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
25.  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

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