Mapping intracellular pH of tumors in vivo using CEST-MRI: methodological development and preclinical investigation

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) allows to non-invasively obtain information about the micromolecular environment of living tissues, particularly, intracellular pH (pHi). In this thesis, a method for quantitative CEST-based pHi mapping was developed enabling, for the first time, compensation of all concomitant effects on CEST signals in tumor tissues, such as unknown concentration changes and superimposing contributions. To this end, a novel model was established enabling direct translation of magnetization exchange rates between protons in proteins and water into pH. This model utilizes (i) the reliable extraction of exchange rates, accomplished by an optimized isolation of measured CEST signals at B0 = 9.4 T, and (ii) a calibration procedure exploiting a newly identified, distinct functional behavior of CEST signals. Porcine brain lysates mimicking in vivo conditions were employed for calibration and to demonstrate reliable pH mapping in the physiologically relevant range of 6.2–8.0. Application in vivo to lesions of tumorbearing mice showed a median pHi of approximately 7.2, further validating the developed method. This novel approach, now, allows to robustly assess the potential of pHi as imaging biomarker for cancer diagnosis or treatment monitoring in preclinical settings, representing an important milestone towards application in humans