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

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• 作者：Alexandre Samouilov ; Olga V. Efimova ; Andrey A. Bobko ; Ziqi Sun ; Sergey Petryakov ; Timothy D. Eubank ; Dmitrii G. Trofimov ; Igor A. Kirilyuk ; Igor A. Grigor鈥檈v ; Wataru Takahashi ; Jay L. Zweier ; Valery V. Khramtsov
• 刊名：Analytical Chemistry
• 出版年：2014
• 出版时间：January 21, 2014
• 年：2014
• 卷：86
• 期：2
• 页码：1045-1052
• 全文大小：406K
• ISSN：1520-6882

文摘

A variable radio frequency proton鈥揺lectron 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鈭?32). 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鈥?.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 卤 0.1), we observed broader pH distribution with acidic mean pH_e (6.8 卤 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 pH_e monitoring, in vivo.