While other studies in the Radiation Biology Branch have shown nitroxides to be efficient antioxidants and radiation protectors, recent studies have shown that they can be used as functional MRI contrast probes. Because nitroxides are paramagnetic their presence in tissue can be monitored non-invasively by MRI. Further the disappearance of nitroxide induced MR intensity enhancement in tissue is a result of intracellular reduction of the nitroxides to the hydroxylamine. By following the rate of reduction of the nitroxide in tissue the redox rate can be determined. This property distinguishes nitroxides as functional MR contrast agents revealing information about the intracellular redox capacity of cells/tissues. We continue to acquire data on nitroxide reduction rates in different normal tissues in mice and various types of tumors. To date we are observed substantial differences among normal tissues. For example, Tempol reduction rate is 3-fold faster in brain as opposed to muscle. Regions around the retina and rectum have extremely fast Tempol reduction rates. Reduction rates among tumors vary by a factor of 2. Further studies have shown that 6-membered ring nitroxides are reduced faster in tissue than 5-membered ring nitroxides. We have shown a direct relationship between tumor oxygen concentration (hypoxia), tumor growth and nitroxide reduction rate. As the tumor grows, the nitroxide reduction rate increases and the oxygen level decreases. Thus, nitroxide reduction rates may reflect the oxygen status in tissues, particularly for tumors. Studies continue to define the various factors involved in nitroxide reduction. We have also demonstrated that certain nitroxide structures when injected into mice or rats provide T1 contrast in the brain, suggesting that nitroxides penetrate the blood brain barrier. We will continue these studies to determine if nitroxide reduction rates in the brain might be useful to predict for radiation-induced neurocognitive damage. Likewise, we will address whether there is a difference in nitroxide reduction in tumors implanted in the brain as opposed to normal brain tissue. Lastly, our studies have also shown that nitroxide based MRI have the potential to guide to appropriate timing of nitroxide administration to yield maximal radioprotection of normal tissues without protection of tumor. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, stroke, prevention of cataracts, inflammatory processes, and aging. Nitroxide based MRI evaluation may have clinical utility in defining the above-mentioned conditions.

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Matsumoto, Ken-ichiro; Hyodo, Fuminori; Anzai, Kazunori et al. (2011) Brain redox imaging. Methods Mol Biol 711:397-419
Davis, Ryan M; Mitchell, James B; Krishna, Murali C (2011) Nitroxides as cancer imaging agents. Anticancer Agents Med Chem 11:347-58
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
Day, Sam E; Kettunen, Mikko I; Cherukuri, Murali Krishna et al. (2011) Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging. Magn Reson Med 65:557-63
Davis, Ryan M; Matsumoto, Shingo; Bernardo, Marcelino et al. (2011) Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape. Free Radic Biol Med 50:459-68
Davis, Ryan M; Sowers, Anastasia L; DeGraff, William et al. (2011) A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector. Free Radic Biol Med 51:780-90
Citrin, Deborah; Cotrim, Ana P; Hyodo, Fuminori et al. (2010) Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 15:360-71
Hyodo, Fuminori; Matsumoto, Shingo; Devasahayam, Nallathamby et al. (2009) Pulsed EPR imaging of nitroxides in mice. J Magn Reson 197:181-5
Hyodo, Fuminori; Soule, Benjamin P; Matsumoto, Ken-Ichiro et al. (2008) Assessment of tissue redox status using metabolic responsive contrast agents and magnetic resonance imaging. J Pharm Pharmacol 60:1049-60
Hyodo, Fuminori; Chuang, Kai-Hsiang; Goloshevsky, Artem G et al. (2008) Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent. J Cereb Blood Flow Metab 28:1165-74

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