A Magnetic Resonance Imaging‐Chemical Exchange Saturation Transfer (MRI‐CEST) Method for the Detection of Water Cycling across Cellular Membranes

Water cycling across the membrane transporters is considered a hallmark of cellular metabolism and it could be of high diagnostic relevance in the characterization of tumors and other diseases. The method relies on the response of intracellular proton exchanging molecules to the presence of extracellular Gd-based contrast agents (GBCAs). Paramagnetic GBCAs enhances the relaxation rate of water molecules in the extracellular compartment and, through membrane exchange, the relaxation enhancement is transferred to intracellular molecules. The effect is detected at the MRI-CEST (Magnetic Resonance Imaging - Chemical Exchange Saturation Transfer) signal of intracellular proton exchanging molecules. The magnitude of the change in the CEST response reports on water cycling across the membrane. The method has been tested on Red Blood Cells and on orthotopic murine models of breast cancer with different degree of malignancy (4T1, TS/A and 168FARN). The distribution of voxels reporting on membrane permeability fits well with the cells' aggressiveness and acts as an early reporter to monitor therapeutic treatments.A Magnetic Resonance Imaging-Chemical Exchange Saturation Transfer (MRI-CEST) method to image and quantify in vivo water cycling across cell membranes is reported. Parametric MRI-maps can be obtained that report, for each voxel, the degree of water permeability across cells. Cell membrane water permeability is a biomarker of cancer aggressiveness and can be used to monitor chemotherapy, as demonstrated in murine models of breast cancers.+image