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

描述(申请人提供)：该项目包括(1)代谢产物运输和代谢的非侵入性成像的新生物工程方法的技术开发，以及(2)这些方法在癌症生物学研究中的应用。非侵入性成像是建立在超极化MRI这一新兴领域的基础上的，它为肿瘤成像应用提供了有价值的新的代谢信息。使用这项技术，我们能够大大增加注射底物的磁共振信号，便于在几秒钟内获得快速代谢数据。这项技术的翻译潜力已经被我们小组最近完成的第一个前列腺癌超极化丙酮酸患者临床试验所证明。与以前只探测代谢转化的超极化成像方法不同，拟议的项目使用扩散加权成像来额外表征丙酮酸及其代谢产物乳酸的运输。这在生物医学上具有非常重要的意义，因为乳酸从细胞外的运输有望预测癌症的侵袭性、进展为转移性疾病和治疗反应，因为这创造了一个酸性环境。目前还没有非侵入性的成像方法来测量体内代谢物的转运。这项提案中的发展是专门为提供和测试这种方法而设计的。这一建议包括进行细胞研究以测量细胞传输介导的对比度的机制，临床前研究以扩散率作为体内传输和代谢的生物标记物，以及开发一种新的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特征。细胞研究和临床前研究都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的表征能力，结果将被用来设计优化的临床方案，并将通过临床前研究进行验证。 拟议的新技术有可能通过改进对侵袭性和转移性疾病进展的预测来改变肿瘤的特征。

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.