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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010476-10
Application #
8552702
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2012
Total Cost
$1,024,143
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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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