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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Kishimoto, Shun; Bernardo, Marcelino; Saito, Keita et al. (2015) Evaluation of oxygen dependence on in vitro and in vivo cytotoxicity of photoimmunotherapy using IR-700-antibody conjugates. Free Radic Biol Med 85:24-32
Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu et al. (2013) EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate. Magn Reson Med 69:1443-50
Subramanian, Sankaran; Chandramouli, Gadisetti V R; McMillan, Alan et al. (2013) Evaluation of partial k-space strategies to speed up time-domain EPR imaging. Magn Reson Med 70:745-53
Subramanian, Sankaran; Devasahayam, Nallathamby; McMillan, Alan et al. (2012) Reporting of quantitative oxygen mapping in EPR imaging. J Magn Reson 214:244-51
Matsumoto, Atsuko; Matsumoto, Ken-ichiro; Matsumoto, Shingo et al. (2011) Intracellular hypoxia of tumor tissue estimated by noninvasive electron paramagnetic resonance oximetry technique using paramagnetic probes. Biol Pharm Bull 34:142-5
Matsumoto, Shingo; Batra, Sonny; Saito, Keita et al. (2011) Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71:6350-9
Matsumoto, Shingo; Yasui, Hironobu; Mitchell, James B et al. (2010) Imaging cycling tumor hypoxia. Cancer Res 70:10019-23
Hyodo, Fuminori; Matsumoto, Shingo; Devasahayam, Nallathamby et al. (2009) Pulsed EPR imaging of nitroxides in mice. J Magn Reson 197:181-5
Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C et al. (2009) The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation. Free Radic Biol Med 47:419-23
Dharmaraj, Christopher D; Thadikonda, Kishan; Fletcher, Anthony R et al. (2009) Reconstruction for Time-Domain In Vivo EPR 3D Multigradient Oximetric Imaging-A Parallel Processing Perspective. Int J Biomed Imaging 2009:528639