Department of Diagnostic Radiology, Hokkaido University Hospital, Sapporo, Japan; Division of UltraHigh Field MRI, Iwate Medical University, Yahaba, Iwate, Japan.
NMR Biomed. 2014 Apr;27(4):453-8. doi: 10.1002/nbm.3081. Epub 2014 Jan 28.
The in vivo quantification of extracellular pH (pHe ) in tumours may provide a useful biomarker for tumour cell metabolism. In this study, we assessed the viability of continuous-wave electron paramagnetic resonance (CW-EPR) spectroscopy with a pH-sensitive nitroxide for the measurement of extracellular tumour pH in a mouse model. CW-EPR spectroscopy (750 MHz) of C3H HeJ mice hind leg squamous cell tumour was performed after intravenous tail vein injection of pH-sensitive nitroxide (R-SG, 2-(4-((2-(4-amino-4-carboxybutanamido)-3-(carboxymethylamino)-3-oxoproylthio)methyl)phenyl)-4-pyrrolidino-2,5,5-triethyl-2,5-dihydro-1Н-imidazol-1-oxyl) during stages of normal tumour growth and in response to a single 10-Gy dose of X-ray irradiation. An inverse relationship was observed between tumour volume and pHe value, whereby, during normal tumour growth, a constant reduction in pHe was observed. This relationship was disrupted by X-ray irradiation and, from 2-3 days post-exposure, a transitory increase in pHe was observed. In this study, we demonstrated the viability of CW-EPR spectroscopy using R-SG nitroxide to obtain high-sensitivity pH measurements in a mouse tumour model with an accuracy of <0.1 pH units. In addition, the measured changes in pHe in response to X-ray irradiation suggest that this may offer a useful method for the assessment of the physiological change in response to existing and novel cancer therapies.
在肿瘤中对细胞外 pH 值（pHe）进行体内定量可能为肿瘤细胞代谢提供一种有用的生物标志物。在这项研究中，我们评估了连续波电子顺磁共振（CW-EPR）光谱与 pH 敏感的氮氧自由基结合用于测量小鼠模型中细胞外肿瘤 pH 值的可行性。在 C3H HeJ 小鼠后腿鳞癌细胞肿瘤的正常生长阶段以及单次 10GyX 射线照射后，通过静脉尾静脉注射 pH 敏感的氮氧自由基（R-SG，2-（4-（（2-（4-氨基-4-羧基丁酰胺基）-3-（羧甲基氨基）-3-氧代丙硫基）甲基）苯基）-4-吡咯烷基-2,5,5-三乙基-2,5-二氢-1H-咪唑-1-氧自由基），进行 CW-EPR 光谱（750MHz）检测。观察到肿瘤体积与 pHe 值之间呈负相关，在正常肿瘤生长过程中，pHe 值持续降低。这种关系被 X 射线照射所破坏，并且在暴露后 2-3 天，观察到 pHe 值短暂增加。在这项研究中，我们证明了使用 R-SG 氮氧自由基的 CW-EPR 光谱法的可行性，该方法可在小鼠肿瘤模型中获得高灵敏度的 pH 值测量，精度小于 0.1pH 单位。此外，测量的 pHe 值响应 X 射线照射的变化表明，这可能为评估现有和新型癌症疗法的生理变化提供一种有用的方法。
