Redox Imaging using Nitroxides and MRI

Division Of Basic Sciences - Nci

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Abstract

Summary 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 are near completion of an extensive study of nitroxide reduction rates in different normal tissues in mice and various types of tumors using a 5-membered ring nitroxide (3-CP) and a 6-membered ring nitroxide, Tempol. Reduction rates were found to vary greatly among normal tissues and selected tumor types. In general, reduction rates were slower for the 5-membered nitroxide than the 6-membered nitroxide. Organs that reduce nitroxides rapidly include the liver, kidney, and brain, while reduction in muscle is quite slow. Along with these studies we have developed techniques to determine the concentration of nitroxides in tissues by MRI. Initial nitroxide concentrations achievable in tissues are in the mM range. Not only can blood pharmacology be conducted, but tissue pharmacology as well. 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. A new nitroxide was identified that exhibits significant uptake in the brain, which we believe will be useful in studies assessing radiation-induced neurocognitive damage and other damage to the brain including ischemia reperfusion injury. This nitroxide was also found to be a very potent protector against radiation damage in normal tissues (mouse). Lastly, nitroxide based MRI is being used to determine the 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.