In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation.
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.
Department of Diagnostic Radiology, Hokkaido University Hospital, Sapporo, Japan; Division of UltraHigh Field MRI, Iwate Medical University, Yahaba, Iwate, Japan.
Jonathan
J
Goodwin
Katsuya
K
Yachi
Masaki
M
Nagane
Hironobu
H
Yasui
Yusuke
Y
Miyake
Osamu
O
Inanami
Andrey A
AA
Bobko
Valery V
VV
Khramtsov
Hiroshi
H
Hirata
D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects; D003497:Cyclic N-Oxides / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D005110:Extracellular Space / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019047:Phantoms, Imaging; D011522:Protons; D047368:Tumor Burden; D014965:X-Rays
D003497:Cyclic N-Oxides; D011522:Protons
EPR; pH; radiotherapy; tumour