Nuclear Overhauser enhancement (NOE) MR imaging of choline phospholipids and their metabolism

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PROJECT SUMMARY Cancer cells by definition are highly proliferative and grow rapidly. In general, the higher the proliferation rate, the more aggressive the tumor tends to be. To maintain the high proliferation rate, membrane choline phospholipid metabolism is upregulated to provide cellular biomass for accelerated growth and maintain viability, which causes changes in the content of both membrane choline phospholipids and their metabolites. Therefore, the content of these molecules have strong association with tumor aggressiveness. To improve the prognosis and treatment-monitoring of cancer, it is highly desirable to have a molecular and metabolic imaging approach to reveal the choline phospholipids and their metabolism. However, although several invasive techniques have been previously developed to study choline phospholipids, there are no methods to date that can assess choline phospholipids and their metabolism in vivo with high sensitivity. Chemical exchange saturation transfer (CEST) MRI is an emerging molecular imaging method with much higher sensitivity than MRS. Recently, we have noticed an in vivo NOE-mediated saturation transfer signal at -1.6 ppm from water, termed NOE(-1.6), which also decrease in tumors. Phantom studies on major tissue components suggest that it is from choline phospholipids. Based on these preliminary data, we hypothesize that (1) the NOE(-1.6) is a saturation transfer effect via dipolar interactions between phospholipid choline head group and water; (2) the reduced NOE(-1.6) signal in tumor is due to the reduced choline phospholipids caused by the upregulated choline phospholipid metabolism. In Aim1, we will validate hypothesis #1 by using modified phospholipid samples, which will suggest the capability of NOE(-1.6) to measure choline phospholipid metabolism in which the choline head group is cleaved by phospholipase enzymes and the NOE(-1.6) signal disappears. In Aim2, we will validate hypothesis #2 by correlating NOE(-1.6) with maps of choline phospholipid contents of whole slices obtained by matrix-assisted laser desorption /ionization imaging mass spectrometry (MALDI IMS) on animal tumor models, which will suggest the capability of NOE(-1.6) to measure altered choline phospholipids and their metabolism in tumors; We will also develop a novel CEST quantification method, termed adiabatic Hyperbolic Secant (HS)-CEST, which substitutes HS inversion pulses in place of conventional saturation pulses, and vary the numbers of HS pulses per unit time to induce different CEST effect in two scans, but vary the HS pulse amplitude to maintain constant average saturation power so that the background direct saturation and MT are same. Subtraction of the two scans will isolate CEST effect from background signals, which solves the challenging issues of non-specificity, B1, and B0 inhomogeneity in conventional CEST imaging. Through these 3 aims, we will provide a unique MRI method for measuring choline phospholipids and their metabolism with high sensitivity, which will allow separate hypothesis-driven preclinical and clinical studies of tumors.