In Vivo Proton–Electron Double-Resonance Imaging of Extracellular Tumor pH Using an Advanced Nitroxide Probe

• Published in: Analytical chemistry (Washington) Vol. 86; no. 2; pp. 1045 - 1052
• Main Authors: Samouilov, Alexandre, Efimova, Olga V, Bobko, Andrey A, Sun, Ziqi, Petryakov, Sergey, Eubank, Timothy D, Trofimov, Dmitrii G, Kirilyuk, Igor A, Grigor’ev, Igor A, Takahashi, Wataru, Zweier, Jay L, Khramtsov, Valery V
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.01.2014
• Subjects: Acidity; acidosis; Animals; Biochemistry; Biocompatibility; Biomedical materials; Breast Neoplasms; Cell Line, Tumor; Cell Survival - drug effects; Cellular biology; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - pharmacology; Diagnostic Imaging - methods; electron paramagnetic resonance spectroscopy; Electron Spin Resonance Spectroscopy - methods; Electrons; Female; glutathione; Glutathione - chemistry; Humans; Hydrogen-Ion Concentration; image analysis; In vivo testing; In vivo tests; mammary glands; Mammary Neoplasms, Experimental - chemistry; Mammary Neoplasms, Experimental - diagnosis; Mice; Mice, Inbred C57BL; monitoring; pathophysiology; Phantoms, Imaging; Protons; radio waves; Resonance; Scientific imaging; Space probes; Spin Labels - chemical synthesis; Surgical implants; Tumors; Water - chemistry
• ISSN: 0003-2700; 1520-6882; 1520-6882
• DOI: 10.1021/ac402230h

A variable radio frequency proton–electron double-resonance imaging (VRF PEDRI) approach for pH mapping of aqueous samples has been recently developed (Efimova et al. J. Magn. Reson. 2011, 209, 227−232 ). A pH map is extracted from two PEDRI acquisitions performed at electron paramagnetic resonance (EPR) frequencies of protonated and unprotonated forms of a pH-sensitive probe. To translate VRF PEDRI to an in vivo setting, an advanced pH probe was synthesized. Probe deuteration resulted in a narrow spectral line of 1.2 G compared to a nondeuterated analogue line width of 2.1 G allowing for an increase of Overhauser enhancements and reduction in rf power deposition. Binding of the probe to the cell-impermeable tripeptide, glutathione (GSH), allows for targeting to extracellular tissue space for monitoring extracellular tumor acidosis, a prognostic factor in tumor pathophysiology. The probe demonstrated pH sensitivity in the 5.8–7.8 range, optimum for measurement of acidic extracellular tumor pH (pHe). In vivo VRF PEDRI was performed on Met-1 tumor-bearing mice. Compared to normal mammary glands with a neutral mean pHe (7.1 ± 0.1), we observed broader pH distribution with acidic mean pHe (6.8 ± 0.1) in tumor tissue. In summary, VRF PEDRI in combination with a newly developed pH probe provides an analytical approach for spatially resolved noninvasive pHe monitoring, in vivo.