Hyperpolarized C-13 Diffusion MRI Measures of Cellular Transport and Metabolism

描述（由申请人提供）：该项目包括（1）用于代谢物转运和代谢的非侵入性成像的新型生物工程方法的技术开发和（2）这些方法在癌症生物学研究中的应用。非侵入性成像是基于超极化MRI的新兴领域，其为癌症成像应用提供了有价值的新代谢信息。使用这种技术，我们能够大大增加注射底物的MR信号，促进在几秒钟内获得快速代谢数据的能力。我们小组最近完成的在前列腺癌患者中使用超极化丙酮酸盐的第一个临床试验已经证明了这种技术的翻译潜力。与以前仅探测代谢转化的超极化成像方法不同，所提出的项目使用扩散加权成像，以额外表征丙酮酸及其代谢产物乳酸的转运。这是非常重要的生物医学意义，因为乳酸盐从细胞中转运出来有希望预测癌症的侵袭性，转移性疾病的进展和对治疗的反应，因为这会产生酸性环境。目前还没有非侵入性成像方法来测量体内代谢物转运。本提案中的发展是专门为提供和测试这些方法而设计的。该提案包括测量细胞转运介导的对比机制的细胞研究，评估扩散率作为体内转运和代谢的生物标志物的临床前研究，以及开发一种新型超极化扩散加权成像方法，该方法可以转化为临床环境，以改善肿瘤侵袭性的表征。细胞和临床前研究还需要开发专门的超极化13C扩散加权方法，因为与传统MRI不同，信号衰减迅速且不可恢复。这些研究将使用癌细胞和癌症模型来评估肿瘤表征能力，结果将用于设计优化的临床方案，并通过临床前研究进行验证。 所提出的新技术有可能通过改善对侵袭性和转移性疾病进展的预测来改变肿瘤表征。

DESCRIPTION (provided by applicant): This project consists of both (1) the technical development of novel bioengineering methods for non-invasive imaging of metabolite transport and metabolism and (2) the application of these methods to study cancer biology. The non-invasive imaging is based on the emerging field of hyperpolarized MRI, which is providing valuable new metabolic information for cancer imaging applications. Using this technique, we are able to greatly increase the MR signal of injected substrates, facilitating the ability to acqure fast metabolic data in seconds. The translation potential of this technique has been demonstrated by the first clinical trial in prostate cancer patients with hyperpolarized pyruvate recently completed by our group. Unlike previous hyperpolarized imaging methods, which only probe metabolic conversions, the proposed projects use diffusion-weighted imaging in order to additionally characterize transport of pyruvate and its metabolic product, lactate. This is of grea biomedical importance since the transport of lactate out of cells has promise for predicting aggressiveness of cancer, progression to metastatic disease and response to therapy, as this creates an acidic environment. There are currently no non-invasive imaging methods to measure metabolite transport in vivo. The developments in this proposal are designed specifically to provide and test such methods. This proposal includes cell studies to measure the mechanisms of cellular transport-mediated contrast, preclinical studies to evaluate diffusivity as a biomarker for transport and metabolism in vivo, and development of a novel hyperpolarized diffusion-weighted imaging method that can be translated into the clinical setting for improved characterization of tumor aggressiveness. Both the cell and preclinical studies also require development of specialized hyperpolarized 13C diffusion-weighted methods because, unlike conventional MRI, the signal decay is rapid and unrecoverable. These studies will use cancer cells and cancer models to evaluate tumor characterization capabilities, and the results will be used to design an optimized clinical protocol, which will be validated through preclinical studies. The proposed novel techniques have the potential to transform tumor characterization through improved prediction of aggressiveness and progression to metastatic disease.