Pulsed electron paramagnetic resonance imaging: Applications in the studies of tumor physiology

Significance:Electron Paramagnetic Resonance imaging (EPRI) is a powerful technique capable of generating images of tissue oxygenation using exogenous paramagnetic probes such as trityl radicals and nitroxyl radicals. Using principles similar to Magnetic Resonance Imaging (MRI) with field gradients, the spatial distribution of the paramagnetic probecan be generated and from its spectral features, spatial maps of oxygen can be obtained from live objects. In this review, the two methods of signal acquisition, image formation/reconstruction will be described. The probes used and its application to study tumor physiology and monitor treatment response with chemotherapy drugs in mouse models of human cancer will be summarized.Recent Advances: By implementing phase encoding/Fourier reconstruction in EPRI in time-domain mode, the frequency contribution to the spatial resolution was avoided and improved images can be obtained. The highresolution EPRI revealed the pO2 change in tumor, which was useful to detect and evaluate the effects of various antitumor therapies. The coregistration with other imaging modalities provided a better understanding of hypoxia related alteration in physiology.Critical Issues: The high power of EPR irradiation and toxicity profile of radical probes are the main obstacles for clinical application. The improvement of pulse sequence may lower the risk.Future Directions:Pulsed EPR oximetry will be a powerfultool to research various disease involving hypoxia such as cancer, ischemic heart diseases, stroke, and diabetes. By optimizing radical probes, it can also be applied for various other purposes such as detecting local acid-base balance or oxidative stress

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients