Phosphonated Trityl Probes for Concurrent in Vivo
Tissue Oxygen and pH Monitoring Using Electron Paramagnetic Resonance-Based
Techniques
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Abstract
Previously we proposed the concept
of dual function pH and oxygen
paramagnetic probes based on the incorporation of ionizable groups
into the structure of persistent triarylmethyl radicals, TAMs (<i>J. Am. Chem. Soc.</i> <b>2007</b>, <i>129</i>, 7240–7241). In this paper, we synthesized an asymmetric
monophosphonated TAM probe with the simplest doublet hfs pattern ideally
suited for dual function electron paramagnetic resonance (EPR)-based
applications. An extraordinary low line width of the synthesized deuterated
derivative, p<sub>1</sub>TAM-D (Δ<i>H</i><sub>pp</sub> ≤ 50 mG, Lorentz line width, ≤20 mG) results in high
sensitivity to <i>p</i>O<sub>2</sub> due to oxygen-induced
line broadening (ΔLW/Δ<i>p</i>O<sub>2</sub> ≈
0.5 mG/mmHg or ≈400 mG/mM); accuracy of <i>p</i>O<sub>2</sub> measurement, ≈1 mmHg). The presence of a phosphono
group in the p<sub>1</sub>TAM-D structure provides pH sensitivity
to its EPR spectra in the physiological range of pH from 5.9 to 8.2
with the ratio of signal intensities of protonated and deprotonated
states being a reliable pH marker (accuracy of pH measurements, ±
0.05). The independent character of pH and [O<sub>2</sub>] effects
on the EPR spectra of p<sub>1</sub>TAM-D provides dual functionality
to this probe. The L-band EPR studies performed in breast tumor-bearing
mice show a significant difference in extracellular pH and <i>p</i>O<sub>2</sub> between tumor and normal mammary gland tissues,
as well as the effect of animal breathing with 100% O<sub>2</sub> on
tissue oxygenation. The developed dual function phosphonated p<sub>1</sub>TAM-D probe provides a unique tool for in vivo concurrent
tissue oxygen and pH monitoring