In vivo monitoring of pH, redox status, and glutathione using L-band EPR for assessment of therapeutic effectiveness in solid tumors

• Published in: Magnetic resonance in medicine Vol. 67; no. 6; pp. 1827 - 1836
• Main Authors: Bobko, Andrey A., Eubank, Timothy D., Voorhees, Jeffrey L., Efimova, Olga V., Kirilyuk, Igor A., Petryakov, Sergey, Trofimiov, Dmitrii G., Marsh, Clay B., Zweier, Jay L., Grigor'ev, Igor A., Samouilov, Alexandre, Khramtsov, Valery V.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2012
• Subjects: Animals; Biomarkers - analysis; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line, Tumor; Electron Spin Resonance Spectroscopy - methods; Female; glutathione; Glutathione - analysis; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Hydrogen-Ion Concentration; in vivo; L-Band EPR; mammary gland; Mice; nitroxides; Oxidation-Reduction; Prognosis; PyMT mice; redox status; solid tumors; Treatment Outcome
• ISSN: 0740-3194; 1522-2594; 1522-2594
• DOI: 10.1002/mrm.23196

Approach for in vivo real‐time assessment of tumor tissue extracellular pH (pHe), redox, and intracellular glutathione based on L‐band EPR spectroscopy using dual function pH and redox nitroxide probe and disulfide nitroxide biradical, is described. These parameters were monitored in PyMT mice bearing breast cancer tumors during treatment with granulocyte macrophage colony‐stimulating factor. It was observed that tumor pHe is about 0.4 pH units lower than that in normal mammary gland tissue. Treatment with granulocyte macrophage colony‐stimulating factor decreased the value of pHe by 0.3 units compared with PBS control treatment. Tumor tissue reducing capacity and intracellular glutathione were elevated compared with normal mammary gland tissue. Granulocyte macrophage colony‐stimulating factor treatment resulted in a decrease of the tumor tissue reducing capacity and intracellular glutathione content. In addition to spectroscopic studies, pHe mapping was performed using recently proposed variable frequency proton–electron double‐resonance imaging. The pH mapping superimposed with MRI image supports probe localization in mammary gland/tumor tissue, shows high heterogeneity of tumor tissue pHe and a difference of about 0.4 pH units between average pHe values in tumor and normal mammary gland. In summary, the developed multifunctional approach allows for in vivo, noninvasive pHe, extracellular redox, and intracellular glutathione content monitoring during investigation of various therapeutic strategies for solid tumors. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.