Project 2: Overhauser enhanced Magnetic Resonance Imaging. (OMRI) Structural and functional abnormality of tumor microvasculature contributes to existent tumor hypoxia, and this feature of solid tumor shows resistance to chemotherapy and radiotherapy, resulting in poor prognosis. Hyperpolarization induction of 1H-H2O strongly depends on the oxygen level surrounding the oxygen sensitive contrast agent TAM in the body. Successful extraction of this oxygen dependent OMRI signal enhancement confers the quantitative oxygen maps in SCC tumor bearing mice. Further extension of this technique is to utilize the oxygen probe TAM itself as a marker of microvascular permeability. Dynamic OMRI scan data fitted to pharmacokinetic models provides endothelial transfer constant Ktrans map as a marker of microvascular permeability, simultaneously with oxygen mapping. Pixel based x-y plot of pO2 vs. Ktrans show the negative correlation, meaning that tumors become hypoxic along with their vasculature becoming leaky. Longitudinal OMRI scans before and after 15 Gy radiation therapy results in the detection of radiation-induced tumor microvascular change, which can be predicted from the oxygen map obtained before the radiation. These findings suggests that the above mentioned simultaneous imaging technique of tumor oxygen and microvascular permeability has the potential to predict and monitor the efficacy of radiation therapy in a non-invasive way. Most tumor diagnostic imaging depends on the common phenotypes that are widely observed in human cancer. Aerobic glycolysis is one of such phenotypes on which clinical FDG-PET also based. Hyperpolarization of 13C-labeled pyruvic acid in the polarizer placed outside the scanner increases its 13C-MRI sensitivity greater than 10,000 times that make us to image the distribution of externally administrated 13C-pruvic acid and its metabolite by a typical MRI. Tumors, unlike normal tissues, prefer aerobic glycolysis than oxidative phosphorylation, resulting in excess lactate production from pyruvate. Though preliminary, we have observed significant lactate production in SCC tumor bearing mice after hyperpolarized 13C-pyruvic acid injection. Our future study will combined this tumor metabolic image with tumor oxygen mapping, which we have already established by both EPR imaging and OMRI, that help to better understand the relationship between tumor oxygen status and its glucose metabolism. Feasibility of tumor metabolic imaging using conventional MRI would provide a new dimension for tumor diagnosis.
