Hyperpolarized 13C Metabolic Imaging of Tumorigenesis in the Liver

项目摘要。 糖酵解和线粒体功能异常是包括肝细胞在内的大多数肝脏疾病的特征 癌（HCC）。尽管有这些代谢特征，但缺乏非侵入性评估方法， 体内代谢通量限制了肝脏疾病的准确表征，反过来又阻碍了肝脏疾病的发展。 新的疗法。在拟议的研究中，我们将采用新型超极化（HP）13 C探头成像 糖酵解是一种在HCC发生和发展中起关键作用的途径。重要的是，我们的跨学科 研究小组在HP 13 C-甘油酸酯探针的设计和应用方面取得了重大进展。 我们已经证明HP [1- 13 C]甘油酸酯是一种无毒底物，具有长T1弛豫时间（60秒）， 这种HP探针对体内肝脏代谢的改变敏感，为临床翻译提供了进展。在 此外，我们最近在肝癌（二乙基亚硝胺[DEN]诱导的大鼠模型）中的研究表明，HP [1- 13 C]甘油酸酯可以基于独特的代谢通量成功地区分HCC和健康肝脏 在癌组织中检测到。鉴于这些进展，我们现在建议HP 13 C-甘油酸酯 可以系统地优化支架以产生第二代HP探针，其提供高度灵敏的 分析肝脏中的酶反应和HCC中异常通量的诊断评估。的 该项目的总体目标是使用HP 13 C-甘油酸盐技术建立体内成像 用于评估HCC发展过程中代谢改变的生物标志物。为此，在目标1中，我们将合成 第二代13 C-甘油酸探针的集中库，专门设计用于增加代谢 从HP实验中获得的信息。在目标2中，我们将分析这些化合物的物理化学性质。 探针，以确定最好的药物，以推进体内HP研究。在目标3中，我们将初步建立 成像生物标志物的HP 13 C-甘油酸酯在DEN大鼠模型，并确定特定的探针，提供明确的 用于区分HCC的度量。这些13 C-甘油酸探针将用于评估逐步进展 在DEN模型中从正常肝脏到HCC。将检查四种病理状态：基线、慢性 炎症、纤维化和HCC。糖酵解的体内指标将在状态之间进行比较，并且这些 结果将通过组织分析进行验证。总的来说，拟议的研究提供了一个创新的战略， 解决临床意义的挑战。最先进的HP探针将用于评估糖酵解改变 在肝癌发生中的作用该技术将反过来提供代表生物学特性的特异性体内生物标志物。 代谢途径，提供了一种非侵入性的方法来评估疾病的进展， 风险患者。

Project Summary. Aberrant glycolysis and mitochondrial function are features of most liver diseases including hepatocellular carcinoma (HCC). Despite these metabolic signatures, the absence of methods to noninvasively assess metabolic fluxes in vivo limits the accurate characterization of liver diseases and in turn impedes the development of new therapies. In the proposed study, we will employ novel hyperpolarized (HP) 13C probes to image glycolysis, a pathway that plays a critical role in HCC onset and progression. Importantly, our cross-disciplinary research team has made significant advancements in the design and application of HP 13C-glycerate probes. We have demonstrated that HP [1-13C]glycerate is a non-toxic substrate with a long T1 relaxation time (60 sec), and this HP probe is sensitive to alterations in liver metabolism in vivo, offering inroads for clinical translation. In addition, our recent studies in HCC (diethylnitrosamine [DEN]-induced rat model) demonstrated that HP [1- 13C]glycerate can successfully distinguish HCC from healthy liver based upon the unique metabolic fluxes detected in the cancerous tissue. Given these advancements, we now propose that the HP 13C-glycerate scaffold can be systematically optimized to yield 2nd generation HP probes, which provide highly sensitive analyses of enzymatic reactions in the liver and diagnostic assessments of abnormal fluxes in HCC. The overarching goal of the proposed project is to use the HP 13C-glycerate technology to establish in vivo imaging biomarkers for assessing altered metabolism during HCC development. To this end, in Aim 1, we will synthesize a focused library of 2nd generation 13C-glycerate probes that are specifically designed to increase the metabolic information obtained from HP experiments. In Aim 2, we will analyze the physicochemical properties of these probes in order to determine top agents to advance towards in vivo HP studies. In Aim 3, we will initially establish imaging biomarkers for HP 13C-glycerates in the DEN rat model and identify specific probes that provide clear metrics for distinguishing HCC. These 13C-glycerate probes will then be used to evaluate a stepwise progression from normal liver to HCC in the DEN model. Four pathological states will be examined: baseline, chronic inflammation, fibrosis, and HCC. In vivo metrics for glycolysis will be compared among the states, and these results will be validated with tissue analyses. Overall, the proposed studies offer an innovative strategy for tackling a challenge of clinical significance. State-of-the-art HP probes will be used to assess altered glycolysis in hepatocarcinogenesis. This technology will in turn provide specific in vivo biomarkers that represent the metabolic pathways of interest in HCC, providing a noninvasive method for assessing disease progression in at- risk patients.