Purpose
In principle, non‐invasive mapping of the intracellular pH (pHi) 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 pHi mapping using endogenous CEST‐MRI, which simultaneously compensates for concentration changes, superimposing CEST signals, magnetization transfer contrast, and spillover dilution.
Theory and Methods
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 MTRRex 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.
Results
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 pHi of approximately 7.2 was found in the lesions of 19 tumor‐bearing mice.
Conclusion
The presented method enables non‐invasive mapping of absolute pHi values in tumors using CEST‐MRI, which was so far prevented by concomitant effects. Consequently, pre‐clinical studies on pHi changes in tumors are possible allowing the assessment of pHi in vivo as a biomarker for cancer diagnosis or treatment monitoring.