Hyperpolarized 13c NMR Studies of Prostate Cancer (RMI)

描述(由申请人提供)： 一项利用超极化13C标记探针的非凡新技术有可能彻底改变MR对体内关键细胞代谢过程的非侵入性观察。动物研究证明，13C标记丙酮酸的极化增强高达40,000倍，为肿瘤代谢物丙氨酸和乳酸的快速成像提供了足够的信号。在这个与GE Healthcare科学家合作的项目中，我们的目标是首次将超极化的13C标记探针(如丙酮酸和乙酸酯)与高场人体磁共振扫描仪、优化的RF接收器和快速光谱成像脉冲序列相结合，以获得前列腺癌13C代谢成像灵敏度约4个数量级的提高。前列腺癌的准确检测和定性仍然是前列腺癌患者个体临床治疗和监测治疗中的主要问题。虽然MRI和1H MR光谱成像的结合在改善前列腺癌治疗前和治疗后的检测和定性方面显示了巨大的前景，但该技术的价值目前受到其较低的空间和光谱分辨率的限制。~(13)C标记的丙酮酸和乙酸酯的使用提供了同时通过多个生化途径(糖酵解、柠檬酸循环和脂肪酸合成)同时评估代谢通量变化的可能性。所有这三条途径都被证明与人类前列腺癌的进化和进展有关的代谢紊乱。在一系列涉及完整的人前列腺活检、用13C标记底物培养的人前列腺细胞系和注射13C标记底物的转基因小鼠的HR-MAS光谱分析中，我们将：(1)确定最能识别前列腺癌的存在和表征其侵袭性的关键13C标记代谢物，以及(2)确定I3C标记代谢物掺入关键代谢物的动力学以及I3C标记代谢物的T1和T2弛豫时间。这些数据将与专门的射频探测器、快速13C光谱成像脉冲序列以及数据重建和分析方案相结合，在前列腺癌患者的初步研究中检测超极化13C标记的代谢成像探针。

DESCRIPTION (provided by applicant): An extraordinary new technique utilizing hyperpolarized 13C labeled probes has the potential to revolutionize the observation of key cellular metabolic processes non-invasively in vivo by MR. Proof-of-principle animal studies have demonstrated up to 40,000 fold polarization enhancements of 13C labeled pyruvate, providing sufficient signal for rapid imaging of the tumor metabolites alanine and lactate. In this collaborative project with GE Healthcare scientists, we aim to, for the first time, combine hyperpolarized 13C labeled probes such as pyruvate and acetate with high field human MR scanners, optimized rf receivers and fast spectroscopic imaging pulse sequences, to obtain an approximately 4 order of magnitude increase in sensitivity for 13C metabolic imaging of prostate cancer. The accurate detection and characterization of prostate cancer remains a major problem in the clinical management of individual prostate cancer patients and in monitoring therapy. While a combination of MRI and 1H MR spectroscopic imaging has shown great promise for improving prostate cancer detection and characterization prior to and following therapy, the value of this technique is currently limited by its coarse spatial and spectral resolution. The use of 13C labeled pyruvate, and acetate provide the potential to simultaneously assess changes in metabolic fluxes through multiple biochemical pathways (glycolysis, citric acid cycle and fatty acid synthesis) simultaneously. All three of these pathways have been shown to have metabolic perturbations associated with the evolution and progression of human prostate cancer. In a series of studies involving ex vivo HR-MAS spectroscopic analysis of intact human prostate biopsies, human prostate cell lines cultured with 13C labeled substrates, and transgenic mice injected with 13C labeled substrate we will; (1) determine the key 13C labeled metabolites that best identify the presence of prostate cancer and characterize its aggressiveness, and (2) determine the kinetics of incorporation of I3C labels into the key metabolites as well as, the T1 and T2 relaxation times of the I3C labeled metabolites. This data will be combined with specialized rf detectors, fast 13C spectroscopic imaging pulse sequences, and data reconstruction and analysis protocols to detect hyperpolarized 13C labeled metabolic imaging probes in preliminary studies of prostate cancer patients.