title: In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe.
abstract: 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 (pH(e)). In vivo VRF PEDRI was performed on Met-1 tumor-bearing mice. Compared to normal mammary glands with a neutral mean pH(e) (7.1 ± 0.1), we observed broader pH distribution with acidic mean pH(e) (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.
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute: ‡Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, and §Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Samouilov
authors.forename: Olga V
authors.initials: OV
authors.lastname: Efimova
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Bobko
authors.forename: Ziqi
authors.initials: Z
authors.lastname: Sun
authors.forename: Sergey
authors.initials: S
authors.lastname: Petryakov
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Eubank
authors.forename: Dmitrii G
authors.initials: DG
authors.lastname: Trofimov
authors.forename: Igor A
authors.initials: IA
authors.lastname: Kirilyuk
authors.forename: Igor A
authors.initials: IA
authors.lastname: Grigor'ev
authors.forename: Wataru
authors.initials: W
authors.lastname: Takahashi
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Valery V
authors.initials: VV
authors.lastname: Khramtsov
mesh_terms: D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000494:pharmacology; D003952:Diagnostic Imaging / Q000379:methods*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D004583:Electrons; D005260:Female; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry* / Q000175:diagnosis; D051379:Mice; D008810:Mice, Inbred C57BL; D019047:Phantoms, Imaging; D011522:Protons; D013113:Spin Labels / Q000138:chemical synthesis; D014867:Water / Q000737:chemistry
chemical_list: D003497:Cyclic N-Oxides; D011522:Protons; D013113:Spin Labels; D014867:Water; D005978:Glutathione