Electron Paramagnetic Resonance Imaging Research Articles

Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair.

Aims: Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors, which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first-line treatment for PDACs but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide, a hypoxia-activated prodrug, has been shown to be effective in combination with GEM, although the mechanism of each drug on the other has not been established. We used mouse xenografts from two cell lines (MIA Paca-2 and SU.86.86) with different tumor microenvironmental characteristics to probe the action of each drug on the other. Results: GEM treatment enhanced survival times in mice with SU.86.86 leg xenografts (hazard ratio [HR] = 0.35, p = 0.03) but had no effect on MIA Paca-2 mice (HR = 0.91, 95% confidence interval = 0.37-2.25, p = 0.84). Conversely, evofosfamide did not improve survival times in SU.86.86 mice to a statistically significant degree (HR = 0.57, p = 0.22). Electron paramagnetic resonance imaging showed that oxygenation worsened in MIA Paca-2 tumors when treated with GEM, providing a direct mechanism for the activation of the hypoxia-activated prodrug evofosfamide by GEM. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in SU.86.86 but not in MIA Paca-2. By the biomarker γH2AX, combination treatment increased the number of double-stranded DNA lesions in vitro for SU.86.86 but not MIA Paca-2. Innovation and Conclusion: The synergy between GEM and evofosfamide appears to stem from the dual action of GEMs effect on tumor vasculature and inhibition by GEM of the homologous recombination DNA repair process. Antioxid. Redox Signal. 39, 432-444.

Use of Electron Paramagnetic Resonance (EPR) to Evaluate Redox Status in a Preclinical Model of Acute Lung Injury.

Patients with hyper- vs. hypo-inflammatory subphenotypes of acute respiratory distress syndrome (ARDS) exhibit different clinical outcomes. Inflammation increases the production of reactive oxygen species (ROS) and increased ROS contributes to the severity of illness. Our long-term goal is to develop electron paramagnetic resonance (EPR) imaging of lungs in vivo to precisely measure superoxide production in ARDS in real time. As a first step, this requires the development of in vivo EPR methods for quantifying superoxide generation in the lung during injury, and testing if such superoxide measurements can differentiate between susceptible and protected mouse strains. In WT mice, mice lacking total body extracellular superoxide dismutase (EC-SOD) (KO), or mice overexpressing lung EC-SOD (Tg), lung injury was induced with intraperitoneal (IP) lipopolysaccharide (LPS) (10mg/kg). At 24h after LPS treatment, mice were injected with the cyclic hydroxylamines 1-hydroxy-3-carboxy-2,2,5,5-tetramethylpyrrolidine hydrochloride (CPH) or 4-acetoxymethoxycarbonyl-1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxylic acid (DCP-AM-H) probes to detect, respectively, cellular and mitochondrial ROS - specifically superoxide. Several probe delivery strategies were tested. Lung tissue was collected up to one hour after probe administration and assayed by EPR. As measured by X-band EPR, cellular and mitochondrial superoxide increased in the lungs of LPS-treated mice compared to control. Lung cellular superoxide was increased in EC-SOD KO mice and decreased in EC-SOD Tg mice compared to WT. We also validated an intratracheal (IT) delivery method, which enhanced the lung signal for both spin probes compared to IP administration. We have developed protocols for delivering EPR spin probes in vivo, allowing detection of cellular and mitochondrial superoxide in lung injury by EPR. Superoxide measurements by EPR could differentiate mice with and without lung injury, as well as mouse strains with different disease susceptibilities. We expect these protocols to capture real-time superoxide production and enable evaluation of lung EPR imaging as a potential clinical tool for subphenotyping ARDS patients based on redox status.

All-Solid-State Batteries with Pre-plated Ultrathin Lithium Metal Enabled by No Pressure Holding and Characterized by In Situ Electron Paramagnetic Resonance Imaging

All-solid-state batteries with ultrathin lithium metal, close to the anode-free solid-state batteries, could achieve high energy density. However, it is not trivial to plate an ultrathin lithium metal layer on a Cu current collector (Cu-CC). In situ electron paramagnetic resonance (EPR) imaging showed that the pre-plating on Cu-CC in a Li-In|Li6PS5Cl|Cu cell without pressure holding produced a lithium metal layer with a small area. However, when a Li-In|Li6PS5Cl|Cu cell was held under a considerable pressure, this cell would produce a lithium metal layer with a large area. The Cu-CC with the ultrathin lithium metal layer of a small surface could be extracted and then assembled with LiNiO2 and Li6PS5Cl to achieve better electrochemical performance compared to that of a large surface, because a small area of the lithium metal layer would lead to fewer side reactions and less consumption of lithium ions. This work suggests the importance of the control of the lithium plating and the observation of lithium plating by in situ EPR imaging.

Direct Measurement and Imaging of Redox Status with Electron Paramagnetic Resonance.

Significance: Fundamental to the application of tissue redox status to human health is the quantification and localization of tissue redox abnormalities and oxidative stress and their correlation with the severity and local extent of disease to inform therapy. The centrality of the low-molecular-weight thiol, glutathione, in physiological redox balance has long been appreciated, but direct measurement of tissue thiol status in vivo has not been possible hitherto. Recent advances in instrumentation and molecular probes suggest the feasibility of real-time redox assessment in humans. Recent Advances: Recent studies have demonstrated the feasibility of using low-frequency electron paramagnetic resonance (EPR) techniques for quantitative imaging of redox status in mammalian tissues in vivo. Rapid-scan (RS) EPR spectroscopy and imaging, new disulfide-dinitroxide spin probes, and novel analytic techniques have led to significant advances in direct, quantitative imaging of thiol redox status. Critical Issues: While novel RS EPR imaging coupled with first-generation molecular probes has demonstrated the feasibility of imaging thiol redox status in vivo, further technical advancements are desirable and ongoing. These include developing spin probes that are tailored for specific tissues with response kinetics tuned to the physiological environment. Equally critical are RS instrumentation with higher signal-to-noise ratio and minimal signal distortion, as well as optimized imaging protocols for image acquisition with sparsity adapted to image information content. Future Directions: Quantitative images of tissue glutathione promise to enable acquisition of a general image of mammalian and potentially human tissue health.

4D-image reconstruction directly from limited-angular-range data in continuous-wave electron paramagnetic resonance imaging

Objective: We investigate and develop optimization-based algorithms for accurate reconstruction of four-dimensional (4D)-spectral-spatial (SS) images directly from data collected over limited angular ranges (LARs) in continuous-wave (CW) electron paramagnetic resonance imaging (EPRI). Methods: Basing on a discrete-to-discrete data model devised in CW EPRI employing the Zeeman-modulation (ZM) scheme for data acquisition, we first formulate the image reconstruction problem as a convex, constrained optimization program that includes a data fidelity term and also constraints on the individual directional total variations (DTVs) of the 4D-SS image. Subsequently, we develop a primal–dual-based DTV algorithm, simply referred to as the DTV algorithm, to solve the constrained optimization program for achieving image reconstruction from data collected in LAR scans in CW-ZM EPRI. Results: We evaluate the DTV algorithm in simulated- and real-data studies for a variety of LAR scans of interest in CW-ZM EPRI, and visual and quantitative results of the studies reveal that 4D-SS images can be reconstructed directly from LAR data, which are visually and quantitatively comparable to those obtained from data acquired in the standard, full-angular-range (FAR) scan in CW-ZM EPRI. Conclusion: An optimization-based DTV algorithm is developed for accurately reconstructing 4D-SS images directly from LAR data in CW-ZM EPRI. Future work includes the development and application of the optimization-based DTV algorithm for reconstructions of 4D-SS images from FAR and LAR data acquired in CW EPRI employing schemes other than the ZM scheme. Significance: The DTV algorithm developed may be exploited potentially for enabling and optimizing CW EPRI with minimized imaging time and artifacts by acquiring data in LAR scans.

A New Application of Spin and Fluorescence Double-Sensor Molecules

EPR imaging techniques are known to be successful tools for mapping living bodies, especially because of the high transparency of tissues in the microwave range. This technique assumes the presence of radicals whose in vivo transport is also controlled by serum albumins. Accordingly, in this study, the interactions between 3-hydroxymethyl-1-oxyl-4-(pyren-1-yl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole radical and the human serum albumin molecules were investigated. To clarify the adsorption processes of this radical onto the surface of human serum albumin (HSA), the interaction of the OMe derivative of the radical was also examined parallel with the studies on the radical-HSA interactions. Considering the solubility issues and also to modulate the transport, inclusion complexes of the radical with a cavitand derivative were also studied. The latter interactions were observed through fluorescence spectroscopy, fluorescence polarization, and by EPR spectroscopy. As a double-sensor molecule, we found that the fluorophore nitroxide is a good candidate as it gave further information about host-guest interactions (fluorescence, fluorescence polarization, and EPR). We also found that in the presence of a cavitand, a complex with greater stability was formed between the sensor molecule and the human serum albumin. Based on these observations, we can conclude that applying this double-sensor (spin, fluorescent) molecule is useful in cases when different interactions can affect the EPR measurements.

Electron Paramagnetic Resonance Image Reconstruction with Total Variation Regularization

This work focuses on the reconstruction of two and three dimensional images of the concentration of paramagnetic species from electron paramagnetic resonance (EPR) measurements. A direct operator, modeling how the measurements are related to the paramagnetic sample to be imaged, is derived in the continuous framework taking into account the physical phenomena at work during the acquisition process. Then, this direct operator is discretized to closely take into account the discrete nature of the measurements and provide an explicit link between them and the discrete image to be reconstructed. A variational inverse problem with total variation regularization is formulated and an efficient resolvant scheme is implemented. The setting of the reconstruction parameters is thoroughly studied and facilitated thanks to the introduction of appropriate normalization factors. Moreover, an a contrario algorithm is proposed to derive the optimal resolution at which the data should be acquired. Finally, an in-depth experimental study over real EPR datasets is done to illustrate the potential and limitations of the presented image reconstruction model.

Investigation of the deactivation and regeneration of an Fe2O3/Al2O3•SiO2 catalyst used in catalytic ozonation of coal chemical industry wastewater

Catalyst deactivation is an ongoing concern for industrial application of catalytic ozonation processes. In this study, we systematically investigated the performance of a catalytic ozonation process employing Fe2O3/Al2O3•SiO2 catalyst for the treatment of coal chemical industry (CCI) wastewater using pilot-scale and laboratory-scale systems. Our results show that the activity of the Fe2O3/Al2O3•SiO2 catalyst for organic contaminant removal deteriorated over time due to formation of a dense and thin carbonaceous layer on the Fe2O3 catalyst surface. EPR and fluorescence imaging analysis confirm that the passivation layer essentially inhibited the O3-catalyst interaction thereby minimizing formation of surficial •OH and associated oxidation of organic contaminants on the catalyst surface. Calcination was demonstrated to be effective in restoring the activity of the catalyst since the carbonaceous layer could be efficiently combusted during calcination to re-establish the surficial •OH-mediated oxidation process. The combustion of the carbonaceous layer and restoration of the Fe layer on the surface on calcination was confirmed based on SEM-EDX, FTIR and thermogravimetric analysis. Cost analysis indicates that regeneration using calcination is economically viable compared to catalyst replacement. The results of this study are expected to pave the way for developing appropriate regeneration techniques for deactivated catalysts and optimising the catalyst synthesis procedure.

Structural Features Governing the Metabolic Stability of Tetraethyl-Substituted Nitroxides in Rat Liver Microsomes.

Nitroxides are potent tools for studying biological systems by electron paramagnetic resonance (EPR). Whatever the application, a certain stability is necessary for successful detection. Since conventional tetramethyl-substituted cyclic nitroxides have insufficient in vivo stability, efforts have recently been made to synthesize more stable, tetraethyl-substituted nitroxides. In our previous study on piperidine nitroxides, the introduction of steric hindrance around the nitroxide moiety successfully increased the resistance to reduction into hydroxylamine. However, it also rendered the carbon backbone susceptible to modifications by xenobiotic metabolism due to increased lipophilicity. Here, we focus on a new series of three nitroxide candidates with tetraethyl substitution, namely with pyrrolidine, pyrroline, and isoindoline cores, to identify which structural features afford increased stability for future probe design and application in in vivo EPR imaging. In the presence of rat liver microsomes, pyrrolidine and pyrroline tetraethyl nitroxides exhibited a higher stability than isoindoline nitroxide, which was studied in detail by HPLC-HRMS. Multiple metabolites suggest that the aerobic transformation of tetraethyl isoindoline nitroxide is initiated by hydrogen abstraction by P450-FeV = O from one of the ethyl groups, followed by rearrangement and further modifications by cytochrome P450, as supported by DFT calculations. Under anaerobic conditions, only reduction by rat liver microsomes was observed with involvement of P450-FeII.

Solanum dulcamara L. Berries: A Convenient Model System to Study Redox Processes in Relation to Fruit Ripening.

The present study provides, for the first time, a physicochemical and biochemical characterization of the redox processes associated with the ripening of Solanum dulcamara L. (bittersweet) berries. Electron Paramagnetic Resonance Spectroscopy (EPRS) and Imaging (EPRI) measurements of reactive oxygen species (ROS) were performed in parallel with the tissue-specific metabolic profiling of major antioxidants and assessment of antioxidant enzymes activity. Fruit transition from the mature green (MG) to ripe red (RR) stage involved changes in the qualitative and quantitative content of antioxidants and the associated cellular oxidation and peroxidation processes. The skin of bittersweet berries, which was the major source of antioxidants, exhibited the highest antioxidant potential against DPPH radicals and nitroxyl spin probe 3CP. The efficient enzymatic antioxidant system played a critical protective role against the deleterious effects of progressive oxidative stress during ripening. Here, we present the EPRI methodology to assess the redox status of fruits and to discriminate between the redox states of different tissues. Interestingly, the intracellular reoxidation of cell-permeable nitroxide probe 3CP was observed for the first time in fruits or any other plant tissue, and its intensity is herein proposed as a reliable indicator of oxidative stress during ripening. The described noninvasive EPRI technique has the potential to have broader application in the study of redox processes associated with the development, senescence, and postharvest storage of fruits, as well as other circumstances in which oxidative stress is implicated.

Trityl Quinodimethane Derivatives as Unimolecular Triple-Function Extracellular EPR Probes for Redox, pH, and Oxygen.

Electron paramagnetic resonance (EPR) spectroscopy and imaging coupled with the use of suitable probes is a promising tool for assessment of the tumor microenvironment (TME). Measurement of multiple TME parameters by EPR is very desirable but challenging. Herein, we designed and synthesized a class of negative-charged trityl quinodimethane MTPs as unimolecular triple-function extracellular probes for redox, pH, and oxygen (O2) levels. Using the deuterated analogue, dMTP5, which has an optimal pKa as well as high sensitivity to bioreduction and O2, we reasonably evaluated pH effects on efflux of reducing agents from HepG2 cells and cellular O2 consumption.

EPR and Related Magnetic Resonance Imaging Techniques in Cancer Research.

Imaging tumor microenvironments such as hypoxia, oxygenation, redox status, and/or glycolytic metabolism in tissues/cells is useful for diagnostic and prognostic purposes. New imaging modalities are under development for imaging various aspects of tumor microenvironments. Electron Paramagnetic Resonance Imaging (EPRI) though similar to NMR/MRI is unique in its ability to provide quantitative images of pO2 in vivo. The short electron spin relaxation times have been posing formidable challenge to the technology development for clinical application. With the availability of the narrow line width trityl compounds, pulsed EPR imaging techniques were developed for pO2 imaging. EPRI visualizes the exogenously administered spin probes/contrast agents and hence lacks the complementary morphological information. Dynamic nuclear polarization (DNP), a phenomenon that transfers the high electron spin polarization to the surrounding nuclear spins (1H and 13C) opened new capabilities in molecular imaging. DNP of 13C nuclei is utilized in metabolic imaging of 13C-labeled compounds by imaging specific enzyme kinetics. In this article, imaging strategies mapping physiologic and metabolic aspects in vivo are reviewed within the framework of their application in cancer research, highlighting the potential and challenges of each of them.

Effect of relative configuration of TEMPO-type nitroxides on ascorbate reduction.

2,2,6,6-Tetramethylpiperidin-N-oxyl (TEMPO)-type nitroxides are susceptible to bioreduction, leading to a loss of radical properties. Although it has been reported that the steric and electronic environments around the N-O moiety of nitroxides affect the reduction, how the relative configuration of nitroxide derivatives alters it is unclear. In this study, we investigated the effect of diastereomers on the radical properties of C2- and C4-disubstituted TEMPO-type nitroxides. We succeeded in isolating the diastereomers of the studied nitroxides for the first time. In addition, we compared the reactivities of nitroxide derivatives with different substituents at the C2 and C4 positions toward ascorbate reduction. We found that the bulky substituents at both C2 and C4 and the electronic effect of C4 affected the reduction of the isomers. C2- and C4-disubstituted nitroxides were administered to mice for electron spin resonance imaging to assess bioreduction in the brain. Similar to the reactivity to reduction in vitro, a difference in the bioreduction of diastereomers was observed in brain tissues. Our research strongly indicates that bioreduction can be controlled by changing the relative configuration, which can be used in the design of nitroxide derivatives for biological applications.

EPRI sparse reconstruction method based on deep learning

Electron paramagnetic resonance imaging (EPRI) is an advanced tumor oxygen concentration imaging method. Now, the bottleneck problem of EPRI is that the scanning time is too long. Sparse reconstruction is an effective and fast imaging method, which means reconstructing images from sparse-view projections. However, the EPRI images sparsely reconstructed by the classic filtered back projection (FBP) algorithm often contain severe streak artifacts, which affect subsequent image processing. In this work, we propose a feature pyramid attention-based, residual, dense, deep convolutional network (FRD-Net) to suppress the streak artifacts in the FBP-reconstructed images. This network combines residual connection, attention mechanism, dense connections and introduces perceptual loss. The EPRI image with streak artifacts is used as the input of the network and the output-label is the corresponding high-quality image densely reconstructed by the FBP algorithm. After training, the FRD-Net gets the capability of suppressing streak artifacts. The real data reconstruction experiments show that the FRD-Net can better improve the sparse reconstruction accuracy, compared with three existing representative deep networks.

Quantitative and space-resolved in situ 1D EPR imaging for the detection of metallic lithium deposits.

The ability to monitor lithium deposition on the anodes in real time is becoming progressively more important due to the development of advanced anode technology. Given the fact that the detrimental Li deposits are always on the micron scale, electron paramagnetic resonance (EPR) happens to be a very effective and selective detection technology due to the skin effect. Here, quantitative in situ 1D EPR imaging is carried out with a magnetic field gradient to achieve a one-dimensional spatial resolution along the Li growth direction in a capillary cell. The quantification of Li deposits is carefully calibrated using a 1,1-diphenyl-2-picrylhydrazyl standard, and a processing method is presented to correct the double integration of the Dysonian line from the metallic Li. The Li deposition processes are compared in two different electrolytes. For the electrolyte containing fluoroethylene carbonate (FEC) additive, the fitting results of Dysonian lines suggest that the plated Li has a larger dimension of the microstructure and the stripping proceeds more uniformly. It thus accounts for the higher Coulombic efficiency in the electrolyte with FEC. In situ EPR imaging also suggests that the Sand's capacity varies with the electrolytes. The forced growth of dendritic Li is carried out at a very large current density using a derivative operando EPR method to monitor the growth locus of the Li dendrites, indicating a tip-growing mechanism. This work can be instructive for those who are engaged in the study of electro-deposited lithium using in situ EPR imaging technology.

Rapid scan EPR: Automated digital resonator control for low-latency data acquisition

Automation has become an essential component of modern scientific instruments which often capture large amounts of complex dynamic data. Algorithms are developed to read multiple sensors in parallel with data acquisition and to adjust instrumental parameters on the fly. Decisions are made on a time scale unattainable to the human operator. In addition to speed, automation reduces human error, improves the reproducibility of experiments, and improves the reliability of acquired data. An automatic digital control (ADiC) was developed to reliably sustain critical coupling of a resonator over a wide range of time-varying loading conditions. The ADiC uses the computational power of a microcontroller that directly communicates with all system components independent of a personal computer (PC). The PC initiates resonator tuning and coupling by sending a command to MC via serial port. After receiving the command, ADiC establishes critical coupling conditions within approximately 5 ms. A printed circuit board resonator was designed to permit digital control. The performance of the resonator together with the ADiC was evaluated by varying the resonator loading from empty to heavily loaded. For the loading, samples containing aqueous sodium chloride that strongly absorb electromagnetic waves were used. A previously reported rapid scan (RS) electron paramagnetic resonance (EPR) imaging instrument was upgraded by the incorporation of ADiC. RS spectra and an in vivo image of oxygen in a mouse tumor model have been acquired using the upgraded system. ADiC robustly sustained critical coupling of the resonator to the transmission line during these measurements. The design implemented in this study can be used in slow-scan and pulsed EPR with modifications.

An iterative reconstruction algorithm without system matrix for EPR imaging

Electron paramagnetic resonance (EPR) imaging is an advanced oxygen imaging modality for oxygen-image guided radiation. The iterative reconstruction algorithm is the research hot-point in image reconstruction for EPR imaging (EPRI) for this type of algorithm may incorporate image-prior information to construct advanced optimization model to achieve accurate reconstruction from sparse-view projections and/or noisy projections. However, the system matrix in the iterative algorithm needs complicated calculation and needs huge memory-space if it is stored in memory. In this work, we propose an iterative reconstruction algorithm without system matrix for EPRI to simplify the whole iterative reconstruction process. The function of the system matrix is to calculate the projections, whereas the function of the transpose of the system matrix is to perform backprojection. The existing projection and backprojection methods are all based on the configuration that the imaged-object remains stationary and the scanning device rotates. Here, we implement the projection and backprojection operations by fixing the scanning device and rotating the object. Thus, the core algorithm is only the commonly-used image-rotation algorithm, while the calculation and store of the system matrix are avoided. Based on the idea of image rotation, we design a specific iterative reconstruction algorithm for EPRI, total variation constrained data divergence minimization (TVcDM) algorithm without system matrix, and named it as image-rotation based TVcDM (R-TVcDM). Through a series of comparisons with the original TVcDM via real projection data, we find that the proposed algorithm may achieve similar reconstruction accuracy with the original one. But it avoids the complicated calculation and store of the system matrix. The insights gained in this work may be also applied to other imaging modalities, for example computed tomography and positron emission tomography.

The optimal 18F-fluoromisonidazole PET threshold to define tumor hypoxia in preclinical squamous cell carcinomas using pO2 electron paramagnetic resonance imaging as reference truth.

To identify the optimal threshold in 18F-fluoromisonidazole (FMISO) PET images to accurately locate tumor hypoxia by using electron paramagnetic resonance imaging (pO2 EPRI) as ground truth for hypoxia, defined by pO2 [Formula: see text] 10mmHg. Tumor hypoxia images in mouse models of SCCVII squamous cell carcinoma (n = 16) were acquired in a hybrid PET/EPRI imaging system 2h post-injection of FMISO. T2-weighted MRI was used to delineate tumor and muscle tissue. Dynamic contrast enhanced (DCE) MRI parametric images of Ktrans and ve were generated to model tumor vascular properties. Images fromPET/EPR/MRI were co-registered and resampled to isotropic 0.5mm voxel resolution for analysis. PET images were converted to standardized uptake value (SUV) and tumor-to-muscle ratio (TMR) units. FMISO uptake thresholds were evaluated using receiver operating characteristic (ROC) curve analysis to find the optimal FMISO threshold and unit with maximum overall hypoxia similarity (OHS) with pO2 EPRI, where OHS = 1 shows perfect overlap and OHS = 0 shows no overlap. The means of dice similarity coefficient, normalized Hausdorff distance, and accuracy were used to define the OHS. Monotonic relationships between EPRI/PET/DCE-MRI were evaluated with the Spearman correlation coefficient ([Formula: see text]) to quantify association of vasculature on hypoxia imaged with both FMISO PET and pO2 EPRI. FMISO PET thresholds to define hypoxia with maximum OHS (both OHS = 0.728 [Formula: see text] 0.2) were SUV [Formula: see text] 1.4 [Formula: see text] SUVmean and SUV [Formula: see text] 0.6 [Formula: see text] SUVmax. Weak-to-moderate correlations (|[Formula: see text]|< 0.70) were observed between PET/EPRI hypoxia images with vascular permeability (Ktrans) or fractional extracellular-extravascular space (ve) from DCE-MRI. This is the first in vivo comparison of FMISO uptake with pO2 EPRI to identify the optimal FMISO threshold to define tumor hypoxia, which may successfully direct hypoxic tumor boosts in patients, thereby enhancing tumor control.

Dual-Mode Tumor Imaging Using Probes That Are Responsive to Hypoxia-Induced Pathological Conditions.

Hypoxia in solid tumors is associated with poor prognosis, increased aggressiveness, and strong resistance to therapeutics, making accurate monitoring of hypoxia important. Several imaging modalities have been used to study hypoxia, but each modality has inherent limitations. The use of a second modality can compensate for the limitations and validate the results of any single imaging modality. In this review, we describe dual-mode imaging systems for the detection of hypoxia that have been reported since the start of the 21st century. First, we provide a brief overview of the hallmarks of hypoxia used for imaging and the imaging modalities used to detect hypoxia, including optical imaging, ultrasound imaging, photoacoustic imaging, single-photon emission tomography, X-ray computed tomography, positron emission tomography, Cerenkov radiation energy transfer imaging, magnetic resonance imaging, electron paramagnetic resonance imaging, magnetic particle imaging, and surface-enhanced Raman spectroscopy, and mass spectrometric imaging. These overviews are followed by examples of hypoxia-relevant imaging using a mixture of probes for complementary single-mode imaging techniques. Then, we describe dual-mode molecular switches that are responsive in multiple imaging modalities to at least one hypoxia-induced pathological change. Finally, we offer future perspectives toward dual-mode imaging of hypoxia and hypoxia-induced pathophysiological changes in tumor microenvironments.

Continuous monitoring of postirradiation reoxygenation and cycling hypoxia using electron paramagnetic resonance imaging.

Reoxygenation has a significant impact on the tumor response to radiotherapy. With developments in radiotherapy technology, the relevance of the reoxygenation phenomenon in treatment efficacy has been a topic of interest. Evaluating the reoxygenation in the tumor microenvironment throughout the course of radiation therapy is important in developing effective treatment strategies. In the current study, we used electron paramagnetic resonance imaging (EPRI) to directly map and quantify the partial oxygen pressure (pO2) in tumor tissues. Human colorectal cancer cell lines, HT29 and HCT116, were used to induce tumor growth in female athymic nude mice. Tumors were irradiated with 3, 10, or 20 Gy using an x‐ray irradiator. Prior to each EPRI scan, magnetic resonance imaging (MRI) was performed to obtain T2‐weighted anatomical images for reference. The differences in the mean pO2 were determined through two‐tailed Student's t‐test and one‐way analysis of variance. The median pO2 60 min after irradiation was found to be lower in HCT116 than in HT29 (9.1 ± 1.5 vs. 14.0 ± 1.0 mmHg, p = 0.045). There was a tendency for delayed and incomplete recovery of pO2 in the HT29 tumor when a higher dose of irradiation (10 and 20 Gy) was applied. Moreover, there was a dose‐dependent increase in the hypoxic areas (pO2 < 10 mmHg) 2 and 24 h after irradiation in all groups. In addition, an area that showed pO2 fluctuation between hypoxia and normoxia (pO2 > 10 mmHg) was also identified surrounding the region with stable hypoxia, and it slightly enlarged after recovery from acute hypoxia. In conclusion, we demonstrated the reoxygenation phenomenon in an in vivo xenograft model study using EPRI. These findings may lead to new knowledge regarding the reoxygenation process and possibilities of a new radiation therapy concept, namely, reoxygenation‐based radiation therapy.