a) Determining and intrinsic spatial, spectral (physiologic) and temporal resolution of EPRI and co-registration with images from MRI. In a multimodality imaging process where different aspects are derived with various imaging modalities such as MRI, EPRI, PET etc, co-registration of these images with different intrinsic resolution characteristics may be required to help in interpreting the EPRI images based on the better resolved MRI images. 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. This allowed for the first time to examine physiological fluctuations in tumors and the effect of anti-angiogenic drugs in minimizing such fluctuations. Further, optimization of imaging experiments allowed the capability to serially monitor changes in tumor physiology over a period of 1 week-10days making it possible to evaluate changes in response to treatment. b) Image formation strategies for absolute pO2 mapping in tumors. The pO2 mapping efforts with EPRI initially started with image formation and reconstruction approaches using filtered back-projection methods. However with the poor spatial resolution inherent with this technique with the broad EPR resonances, we resorted to a Fourier imaging approach using the Single Point Imaging (SPI) strategy yet using static magnetic field gradients. With this approach, we were able to realize useful spatial and physiologic resolutions. However, the magnetic susceptibility inhomogeneity inherent with the EPRI using the SPI modality makes it difficult to compare imaging results obtained with different scanners or even different resonators with the same scanners. To overcome this difficulty, we have developed a novel image formation strategy by implementing Electron Spin Echo detection in EPRI with the Fourier image encoding approach of SPI. Pulse sequences were developed using a puklse programmer designed on a LabView platform with a time resolution of 1 ns and pulse widths which can be incremented in 20 ns steps. Images were generated using the echo detection and we were able to obtain images of absolute pO2 in phantom objects and in vivo which were not subject to artifacts associated with magnetic field inhomogeneities. c) Strategies for imaging larger sized objects: While the image formation and reconstruction approaches developed will be applicable for imaging tissue oxygen in small animals and even accessible tumors in humans such as in breast, head and neck, prostate etc, mapping pO2 in deep seated tumors requires the use of radiofrequency (RF) excitation at powers which may exceed the permitted levels. To develop RF excitation strategies for human applications in deep seated tumors, we have incorporated techniques utilized in solid state NMR spectroscopy and cell phone industry to use tailored pulse sequences which have constant amplitude but different phases with low excitation power. Pulse sequences such as this use RF peak powers several orders of magnitude lower than conventional methods and yet can detect EPRI signals. To enable this, we have incorporated an arbitrary wave form generator with a 83 ps time resolution and a transmit/receive switch with a recovery time of 50 ns. With this capability, we are evaluating aspects related to sensitivity of detection to understand the next steps in implementing this technique for human use. d) Assessment of dynamics in tumor physiology by EPRI. After developing image formation strategies to minimize the time taken for a 3-d image of tumor pO2 to be less than 3 minutes, we have conducted tumor oxygen imaging in a time window of 30 minutes to examine regions of tumor for fluctuations in oxygen. We show for the first time that there exist in tumors, regions where oxygen status reflects behaviour typical of cycling hypoxia and regions which are chronically. e) Temporal profile of tumor physiology when treated with anti-angiogenic drugs. Using the capability of EPR to monitor changes in tumor pO2 and blood volume when treated with suntinib, we found that there is a period aft6er 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.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Matsumoto, Ken-Ichiro; Kishimoto, Shun; Devasahayam, Nallathamby et al. (2018) EPR-based oximetric imaging: a combination of single point-based spatial encoding and T1 weighting. Magn Reson Med 80:2275-2287
Matsumoto, Ken-Ichiro; Hyodo, Fuminori; Mitchell, James B et al. (2018) Effect of body temperature on the pharmacokinetics of a triarylmethyl-type paramagnetic contrast agent used in EPR oximetry. Magn Reson Med 79:1212-1218
Kishimoto, Shun; Krishna, Murali C; Khramtsov, Valery V et al. (2018) In Vivo Application of Proton-Electron Double-Resonance Imaging. Antioxid Redox Signal 28:1345-1364
Scroggins, Bradley T; Matsuo, Masayuki; White, Ayla O et al. (2018) Hyperpolarized [1-13C]-Pyruvate Magnetic Resonance Spectroscopic Imaging of Prostate Cancer In Vivo Predicts Efficacy of Targeting the Warburg Effect. Clin Cancer Res 24:3137-3148
Matsumoto, Ken-Ichiro; Mitchell, James B; Krishna, Murali C (2018) Comparative studies with EPR and MRI on the in vivo tissue redox status estimation using redox-sensitive nitroxyl probes: influence of the choice of the region of interest. Free Radic Res 52:248-255
Matsumoto, Shingo; Kishimoto, Shun; Saito, Keita et al. (2018) Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice. Cancer Res 78:3783-3792
Matsuo, Masayuki; Kawai, Tatsuya; Kishimoto, Shun et al. (2018) Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation. Oncotarget 9:25089-25100
Kishimoto, Shun; Matsumoto, Ken-Ichiro; Saito, Keita et al. (2018) Pulsed Electron Paramagnetic Resonance Imaging: Applications in the Studies of Tumor Physiology. Antioxid Redox Signal 28:1378-1393
Takakusagi, Yoichi; Kishimoto, Shun; Naz, Sarwat et al. (2018) Radiotherapy Synergizes with the Hypoxia-Activated Prodrug Evofosfamide: In Vitro and In Vivo Studies. Antioxid Redox Signal 28:131-140
Yasui, Hironobu; Kawai, Tatsuya; Matsumoto, Shingo et al. (2017) Quantitative imaging of pO2 in orthotopic murine gliomas: hypoxia correlates with resistance to radiation. Free Radic Res 51:861-871

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