IMAGING OF HYPERPOLARIZED SUBSTRATES IN ANIMAL MODELS OF CANCER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 体内代谢的测量对于癌症的诊断和监测具有突出的潜力，因为代谢准确地报告了肿瘤的生物学状态。癌症成像的一个持续挑战是增加可以在体内观察到的与肿瘤生长、遗传学或对治疗的反应相关的生物学特征的数量。到目前为止，癌症中的“代谢成像”仅限于营养摄取的快照（例如FDG-PET）和一些丰富代谢物（如乳酸盐和胆碱）的稳态水平（磁共振光谱）。原则上，基于核磁共振（NMR）的成像可以显着拓宽肿瘤代谢的视野，因为它允许用户观察13 C从标记探针转移到活组织中的酶促反应产物。NMR可以与基于MRI的成像相结合，将代谢活动映射到精确的解剖位置，包括肿瘤。将NMR光谱扩展到临床实践的主要障碍是13 C核自旋的低丰度和灵敏度，导致低信噪比。然而，最近，动态核极化（“超极化”）的出现大大增加了实时的可行性，NMR为基础的体内代谢成像。在这种技术中，13 C核自旋态的极化通过从自由基的未成对电子的高自旋极化转移而大大增强。虽然是短暂的，但这种偏振增益转化为信噪比的10，000倍（或更大）改善。 我们假设，超极化的自然发生的代谢产物，如丙酮酸盐将使我们能够监测在动物模型中的癌症活肿瘤的代谢。该项目的主要目标是开发获得荷瘤小鼠代谢活动高分辨率图像的方法。该提案借鉴了我们使用稳定同位素方法研究肿瘤代谢和使用超极化监测离体细胞和灌注器官中代谢活动的经验。拟议的活动是朝着我们的目标发展超极化作为诊断人类癌症和监测其对治疗反应的临床工具的下一个合乎逻辑的步骤。该项目将受益于研究资源内的并行活动。 拟议的实验将涵盖肿瘤生长的小鼠模型的三个主要类别：皮下异种移植物，在原位部位植入的肿瘤，和肿瘤发生的转基因模型。 目的有三：1）成像癌细胞系来源的皮下肿瘤中的丙酮酸代谢。2)原位神经胶质瘤中丙酮酸代谢成像，和3）自发性乳腺癌小鼠模型中丙酮酸代谢成像。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Measurement of in vivo metabolism has outstanding potential for the diagnosis and monitoring of cancer, because metabolism accurately reports the tumor's biological state. An ongoing challenge in cancer imaging is to increase the number of biological features that can be viewed in vivo and correlated with tumor growth, genetics, or response to therapy. So far, "metabolic imaging" in cancer has been limited to snapshots of nutrient uptake (e.g. FDG-PET) and steady-state levels of a few abundant metabolites like lactate and choline (magnetic resonance spectroscopy). In principle, imaging based on nuclear magnetic resonance (NMR) could significantly widen the view of tumor metabolism because it would allow the user to observe the transfer of 13C from labeled probes to products by enzymatic reactions in live tissue. NMR can be integrated with MRI-based imaging to map metabolic activities to precise anatomic locations, including tumors. The major obstacle to extending NMR spectroscopy into clinical practice is the low abundance and sensitivity of the 13C nuclear spin, resulting in a low signal-to-noise ratio. Recently, however, the advent of dynamic nuclear polarization ("hyperpolarization") has drastically increased the feasibility of real-time, NMR-based imaging of metabolism in vivo. In this technique, polarization of the 13C nuclear spin state is greatly enhanced by transfer from the high spin polarization of an unpaired electron from a free radical. Although transient, this gain in polarization translates into a 10,000-fold (or greater) improvement in signal-to-noise ratio. We hypothesize that hyperpolarization of naturally-occurring metabolites like pyruvate will enable us to monitor the metabolism of live tumors in animal models of cancer. The major goal of the project is to develop methods to obtain high-resolution images of metabolic activity in tumor-bearing mice. The proposal draws on our experience using stable isotope methods to study tumor metabolism and using hyperpolarization to monitor metabolic activity in isolated cells and perfused organs. The proposed activities are the next logical step towards our goal of developing hyperpolarization as a clinical tool for diagnosing human cancer and monitoring its response to therapy. This project will benefit from concurrent activities within the Research Resource. The proposed experiments will cover the three major categories of mouse models of tumor growth: subcutaneous xenografts, tumors implanted at an orthotopic site, and a transgenic model of tumorigenesis. There are three aims: 1) Image pyruvate metabolism in subcutaneous tumors derived from cancer cell lines. 2) image pyruvate metabolism in orthotopic gliomas, and 3) image pyruvate metabolism in a mouse model of spontaneous breast cancer.