In vivo proton-electron double-resonance imaging of extracellular tumor pH using an advanced nitroxide probe

Alexandre Samouilov, Olga V. Efimova, Andrey A. Bobko, Ziqi Sun, Sergey Petryakov, Timothy D. Eubank, Dmitrii G. Trofimov, Igor A. Kirilyuk, Igor A. Grigor'Ev, Wataru Takahashi, Jay L. Zweier, Valery V. Khramtsov

Research output: Contribution to journalArticlepeer-review

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 (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.

Original languageEnglish (US)
Pages (from-to)1045-1052
Number of pages8
JournalAnalytical Chemistry
Volume86
Issue number2
DOIs
StatePublished - Jan 21 2014
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry

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