Mapping intracellular pH in tumors using amide and guanidyl CEST-MRI at 9.4 T

In principle, non-invasive mapping of the intracellular pH (pH_i ) in vivo is possible using endogenous chemical exchange saturation transfer (CEST)-MRI of the amide and guanidyl signals. However, the application for cancer imaging is still impeded, as current state-of-the-art approaches do not allow for simultaneous compensation of concomitant effects that vary within tumors. In this study, we present a novel method for absolute pH_i mapping using endogenous CEST-MRI, which simultaneously compensates for concentration changes, superimposing CEST signals, magnetization transfer contrast, and spillover dilution.

Compensation of the concomitant effects was achieved by a ratiometric approach (i.e. the ratio of one CEST signal at different B₁ ) in combination with the relaxation-compensated inverse magnetization transfer ratio MTR_Rex and a separate first-order polynomial-Lorentzian fit of the amide and guanidyl signals at 9.4 T. Calibration of pH values was accomplished using in vivo-like model suspensions from porcine brain lysates. Applicability of the presented method in vivo was demonstrated in n = 19 tumor-bearing mice.

In porcine brain lysates, measurement of pH was feasible over a broad range of physiologically relevant pH values of 6.2 to 8.0, while being independent of changes in concentration. A median pH_i of approximately 7.2 was found in the lesions of 19 tumor-bearing mice.

The presented method enables non-invasive mapping of absolute pH_i values in tumors using CEST-MRI, which was so far prevented by concomitant effects. Consequently, pre-clinical studies on pH_i changes in tumors are possible allowing the assessment of pH_i in vivo as a biomarker for cancer diagnosis or treatment monitoring.