Time Domian Electron Paramagnetic Resonance Imaging

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a) Determining and intrinsic spatial, spectral (physiologic) and temporal resolution of EPRI and co-registration with images from MRI. Improving the temporal resolution using ?partial k-space? image data acquisition strategiesThe fundamental spectrometer dependent factors governing the spatial, spectral and temporal resolutions have been studied to understand the practically realizable resolutions in vivo experiments. This is an important factor which when analyzed will permit conducting in vivo experiments to ask fundamental questions pertaining to the dynamics of physiology and physiological fluctuations in tumors, which has not been possible till now. We have critically examined factors involved in determining the intrinsic resolution in EPRI and developed image formation strategies to optimize the EPRI data sets for optimal spatial, temporal and spectral (physiologic) resolutions. With an understanding of the factors governing the spatial, spectral and temporal resolutions, we have been able to optimize and improve the same. Additionally, we have borrowed concepts from MRI such as compressed sensing and partial k-space imaging strategies and have been able to collect images in as little as 1 minute for a full 3-dimensional image data without sacrificing the spatial and spectral dimensions. With this capability, we have been able to probe the subtle temporal fluctuations in tumor pO2 and also distinguish chronic and cycling hypoxia. We have also implemented imaging of pO2 in glioblastoma models in mice where for the first time we have been able to demonstrate the feasibility of pO2 maps.b) Strategies for imaging larger sized objects:We have redesigned a low field MRI scanner to operate as an EPRI pO2 imager by integrating the EPR RF chain and controlling the gradient amplifiers. The magnet has an 80 cm bore and permits the study of larger objects. We have developed imaging gantries where it is possible to collect pO2 images and move the object to an adjacent MRI scanner operating at 1.0 T to collect anatomical images which can be co-registered with pO2 maps. This has made it possible to increase the number of studies which can be performed. c) Temporal profile of tumor physiology when treated with drugs which impact microcirculation. Using the capability of EPR to monitor changes in tumor pO2 and blood volume when treated with rapamycin, we found that there is a period after initiating treatment where there is a transient increase in tumor pO2 with an accompanying decrease in blood vessel density consistent with the hypothesis of vascular re-normalization in addition to inhibiting mTOR pathways.d) Identification of strategies to induce temporary hypoxia to enhance the efficacy of hypoxic cytotoxins:We have been conducting metabolic MRI using hyperpolarized pyruvic acid as the tracer. We examined the effect of bolus pyruvate injection on tumor pO2 profiles and demonstrated that pyruvate induces hypoxia immediately after a bolus dose which is sustained for 4 hours. This is an important finding in using hypoxia sensitive drugs. We found that in hypoxic tumors, the efficacy of hypoxic cytotoxins such as TH-302 is enhanced by prior treatment with pyruvate which induces hypoxia transiently. The enhanced efficacy of TH-302 is explained as bring the tumor hypoxia into radiobiologic hypoxia.