Exploring combined hyperpolarized 13C MRI with liver-specific gadolinium contrast agents for improved metabolic assessment of liver tumors

摘要 本项目的目标是开发一种新的超极化(HP)~(13)C磁共振成像和光谱方法 允许对肿瘤代谢进行有针对性的评估的肝脏肿瘤。肝脏肿瘤的代谢成像是 出于几个原因，这在临床上很重要。肝肿瘤通常采用局部区域疗法(放射、 化学或热消融)，需要对肿瘤反应和复发进行密切评估。另外， 已知代谢变化先于许多治疗后的大小变化，尤其是放射治疗。惠普 ~(13)C核磁共振是一种很有前途的新兴分子成像工具，具有许多潜在的癌症应用前景 包括肝脏肿瘤的影像检查。然而，超极化的MR信号并不是特定于器官和组织类型的。 例如，在受损的肝脏中，目前无法确定观察到的超极化信号 来自肝细胞或炎性细胞。同样，由于大多数卫星的空间分辨率有限， HP MRI研究，同样不可能将小肿瘤产生的信号从周围分离出来 非肿瘤性肝细胞，也具有较高的代谢活性。这种缺乏特异性限制了潜在的 HP13C MRI用于监测肝肿瘤的生存能力和对治疗的反应。因此，有一种 未满足的需要，以提高超极化13C磁共振测量肝脏肿瘤的细胞特异性。我们 提出将超极化~(13)C MRI与肝脏肿瘤相结合，将超极化~(13)C MRI定位于肝脏肿瘤。 选择性地被带入肝细胞的特定的基于Gd的造影剂。因为特工被定位在 在肝细胞内，而不是在肿瘤细胞内，它将缩短超极化的T1(从而抑制信号) 位于肝细胞内的化合物，并保存来自肿瘤细胞的信号(不包括 Gd造影剂)。这项探索性研究旨在检验和论证这一方法的可行性。 接近。使用转移性结肠癌的动物模型，将进行超极化采集 Gd造影剂给药前后。我们会找到对比剂的剂量和时间 注射最大限度地增加从肝肿瘤细胞接收的信号量，同时最小化 从邻近的正常肝脏收到的信号。据我们所知，这将是第一次 以特定细胞类型为靶点的超极化13C造影剂。此外， 使用竞争对手的分子成像技术，如 作为FDG-PET，这表明这项技术可能在肝脏超极化13C MRI中发挥独特的作用 肿瘤成像。最后，如果这项工作成功，这项技术应该可以迅速转化为未来的研究 在人类身上。

Abstract The goal of this project is to develop a new method for hyperpolarized (HP) 13C MR imaging and spectroscopy of liver tumors that permits targeted evaluation of tumor metabolism. Metabolic imaging of liver tumors is clinically important for several reasons. Liver tumors are often treated with local-regional therapies (radiation, chemical or thermal ablation), requiring close evaluation for tumor response and recurrence. Additionally, metabolic changes are known to precede size changes following many treatments, especially radiotherapy. HP 13C MRI is a promising emerging molecular imaging tool for with numerous potential applications to cancer imaging including liver tumors. However, the hyperpolarized MR signal is not specific for organ and tissue type. In the injured liver, for example, it is currently impossible to determine if the observed hyperpolarized signal comes from hepatocytes or from inflammatory cells. Similarly, because of the limited spatial resolution of most HP MRI studies, it is likewise impossible to separate the signal arising from small tumors from surrounding non-tumorous hepatocytes, which also have high metabolic activity. This lack of specificity limits the potential for HP 13C MRI to monitor the viability of liver tumors and their responses to treatment. There is therefore an unmet need to increase the cellular specificity of hyperpolarized 13C MRI measurements of liver tumors. We propose to target hyperpolarized 13C MRI to liver tumors by combining hyperpolarized 13C MRI with a liver- specific gadolinium-based contrast agent that is selectively taken into liver cells. Because the agent is located within liver cells but not tumor cells, it will shorten the T1 (and therefore quench the signal) from hyperpolarized compounds located within liver cells and preserve signal arising from tumor cells (which exclude the gadolinium contrast agent). This exploratory study is intended to test and demonstrate the feasibility of this approach. Using an animal model of metastatic colon cancer, hyperpolarized acquisitions will be performed before and after administration of the gadolinium contrast agent. We will find the dose and timing of contrast injection that maximizes the amount of signal received from liver tumor cells while minimizing the amount of signal received from adjacent normal liver. To our knowledge, this will be the first combination of hyperpolarized 13C imaging with gadolinium contrast agents targeted to a particular cell type. In addition, the suppression of background liver signal is not possible using competing molecular imaging technologies such as FDG-PET, which suggests this technology may create a unique role for hyperpolarized 13C MRI in liver tumor imaging. Finally, if this work is successful, this technology should be rapidly translatable to future studies in humans.