High resolution pH_e imaging of rat glioma using pH-dependent relaxivity

Previous studies using MR spectroscopy have shown that the extracellular pH (pH_e) of tumors is acidic compared to normal tissues. This has a number of important sequelae that favor the emergence of more aggressive and therapy-resistant tumors. New MRI methods based on pH-sensitive T₁ relaxivity are an attractive alternative to previous spectroscopic methods, as they allow improvements in spatial and temporal resolution. Recently, pH-dependent GdDOTA-4AmP^5- and a pH-independent analog, GdDOTP ^5-, were used to image renal pH in mice. The current study has used a similar approach to image pH_e in rat gliomas. Significant differences were observed compared to the renal study. First, the relaxivity of GdDOTP^5- was found to be affected by the higher extracellular protein content of tumors. Second, the pixel-by-pixel analysis of the GdDOTP ^5- and GdDOTA-4AmP^5- pharmacokinetics showed significant dispersion, likely due to the temporal fluctuations in tumor perfusion. However, there was a robust correlation between the maximal enhancements produced by the two boluses. Therefore, to account for the local time-courses differences, pH_e maps were calculated at the time of maximal enhancement in each pixel. Finally, the comparison of the pH_e and the time to maximal intensity maps revealed an inverse relationship between pH_e and tumor perfusion.