Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape

Nitroxides are a class of stable free radicals that have several biomidical applications including radioprotection and noninvasive asessment of tissue redox status. For both of these applicaitons, it is necessary to understand the in vivo biodistribution and reduction of nitroxides. In this study, magnetic resonance imaging was used to compare tissue accumulation (concentration) and reduction of two commonly studied nitroxides: the piperidine nitroxide Tempol and pyrrolidine nitroxide 3-CP. It was found that 3-CP was reduced 3 to 11 times slower (depending on the tissue) than Tempol in vivo and that maximum tissue concentration varies substantially between tissues (0.6-7.2 mM). For a given tissue, the maximum concentration usually did not vary betweeen the two nitroxides. Furthermore, using electron paramagnetic resonance spectroscopy, we showed that the nitroxide reduction rate depends only weakly on cellular pO2 in the oxygen range expected in vivo. These observations, taken with the marked variation in nitorxide reductin rates observed between tissues, suggest that tissue pO2 is not a major determinant of the nitoride reduction rate in vivo. For the purpose of redox imaiging, 3-CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo

The influence of tumor oxygenation on (18)F-FDG (fluorine-18 deoxyglucose) uptake: a mouse study using positron emission tomography (PET).

International audienceBACKGROUND: This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of (18)F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET). RESULTS: Tumor-bearing mice (squamous cell carcinoma) maintained at 37 degrees C were studied while breathing either normal air or carbogen (95% O(2), 5% CO2), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential (18)F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of (18)F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest (18)F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, (18)F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation. CONCLUSION: Tumor (18)F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance (18)F-FDG functional imaging

Intracellular Hypoxia of Tumor Tissue Estimated by Noninvasive Electron Paramagnetic Resonance Oximetry Technique Using Paramagnetic Probes

Electron paramagnetic resonance (EPR) oximetry at 700 MHz operating frequency employing a surface coil resonator is used to assess tissue partial pressure of oxygen (pO2) using paramagnetic media whose linewidth and decay constant are related to oxygen concentration. Differences in extracellular and intracellular pO2 in squamous cell carcinoma (SCC) tumor tissue were tested using several types of water-soluble paramagnetic media, which localize extracellularly or permeate through the cell membrane. The nitroxide carboxy-PROXYL (CxP) can only be distributed in blood plasma and extracellular fluids whereas the nitroxides carbamoyl-PROXYL (CmP) and TEMPOL (TPL) can permeate cell membranes and localize intracellularly. EPR signal decay constant and the linewidth of the intravenously administered nitroxides in SCC tumor tissues implanted in mouse thigh and the contralateral normal muscle of healthy mice breathing gases with different pO2 were compared. The pO2 in the blood can depend on the oxygen content in the breathing gas while tissue pO2 was not directly influenced by pO2 in the breathing gas. The decay constants of CmP and TPL in tumor tissue were significantly larger than in the normal muscles, and lower linewidths of CmP and TPL in tumor tissue was observed. The SCC tumor showed intracellular hypoxia even though the extracellular pO2 is similar to normal tissue in the peripheral region

Intracellular hypoxia of tumor tissue estimated by noninvasive electron paramagnetic resonance oximetry technique using paramagnetic probes

Electron paramagnetic resonance (EPR) oximetry at 700 MHz operating frequency employing a surface coil resonator is used to assess tissue partial pressure of oxygen (pO2)using paramagnetic media whose linewidth and decay constant are related to oxygen concentration. Differences in extracellular and intracellular pO2 in squamous cell carcinoma (SCC) tumor tissue were tested using several types of water-soluble paramagnetic media, which localize extracellularly or permeate through the cell membrane. The nitroxide carboxy-PROXYL (CxP) can only be distributed in blood plasma and extracellular fluids whereas the nitroxides carbamoyl-PROXYL (CmP) and TEMPOL (TPL) can permeate cell membranes and localize intracellularly. EPR signal decay constant and the linewidth of the intravenously administered nitroxides in SCC tumor tissues implanted in mouse thigh and the contralateral normal muscle of healthy mice breathing gases with different pO2 were compared. The pO2 in the blood can depend on the oxygen content in the breathing gas while tissue pO2 was not directly influenced by pO2 in the breathing gas. The decay constants of CmP and TPL in tumor tissue were significantly larger than in the normal muscles, and lower linewidths of CmP and TPL in tumor tissue was observed. The SCC tumor showed intracellular hypoxia even though the extracellular pO2 is similar to normal tissue in the peripheral region

The influence of tumor oxygenation on (18)F-FDG (fluorine-18 deoxyglucose) uptake: a mouse study using positron emission tomography (PET).

International audienceBACKGROUND: This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of (18)F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET). RESULTS: Tumor-bearing mice (squamous cell carcinoma) maintained at 37 degrees C were studied while breathing either normal air or carbogen (95% O(2), 5% CO2), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential (18)F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of (18)F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest (18)F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, (18)F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation. CONCLUSION: Tumor (18)F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance (18)F-FDG functional imaging