Development and Translation of D-glucose as a Diagnostic Agent for MRI of Cancer

项目摘要/摘要 每年，大约有5000万剂合成造影剂被注射到 世界各地的患者在接受核磁共振检查时。虽然这些毒剂非常安全，但它们有可能 对一些患者有不良反应。此外，当手术进行时，它们可能会在脑组织和骨组织中积聚 反复发生，风险尚不清楚。目前，所有的核磁共振试剂都需要某种化学标记，即 对磁性金属或铁磁性金属，或最近，与超极化磁性同位素。这个项目的总体目标是 BRG是作为MRI造影剂的简单D-葡萄糖的发展。使用这样一种自然的 试剂安全，不干扰标准解剖图像的对比度，成本低， 能够在短时间内进行重复研究。我们将首先为大脑开发这项技术 癌症，之后，它可以调整为一般用途。造影剂被用来显示肿瘤解剖结构 以及生理学，它可以提供关于恶性肿瘤和治疗反应的信息。我们的假设是 D-葡萄糖作为一种不可熔的MRI造影剂可以提供关于肿瘤的三个重要方面的信息 生理，即传递、摄取(包括血脑屏障破坏的影响)和新陈代谢。如果我们的 开发是成功的，由于D-葡萄糖已经广泛应用，转化为临床应用将会很快 用于其他适应症(例如糖尿病的葡萄糖耐量试验)，其安全性已得到很好的证实。 我们的初步数据显示，在动物模型中， 11.7T，脑肿瘤患者7T和3T。然而，3T存在技术问题，因为减少了 效果大小，需要为运动校正、数据采集和分析开发额外的技术。 我们对这一BRG的总体开发目标是优化和标准化D-葡萄糖作为输液剂的使用 临床野强度为3T的肿瘤生理学诊断和预后成像造影剂。这个 具体目标是(1)设计和优化快速全脑动态MRI饱和脉冲序列技术 为了检测基于D-葡萄糖的(A)T2弛豫效应，(B)联合化学交换饱和转移 (2)设计和优化与CEST-MRI兼容的运动校正方法 用于动态扫描，包括导航回波制导和深度学习分析；(3)设计优化 用于可视化肿瘤增强和获取的半定量和定量数据分析方法 肿瘤D-葡萄糖转运、摄取和代谢指标；(4)AIMS 1-3和AIMS方法标准化 演示可重复性和再现性，以使用动态磁共振临床方案来结束工作 葡萄糖增强(DGE)磁共振成像。以最佳的效率、适当的验证和临床应用来实现这些目标 与此相关，我们在核磁共振物理(脉冲序列)领域建立了一个多学科专家团队 发展)、临床肿瘤学、生物统计学和内分泌学，这将使用几个 肯尼迪·克里格研究所和约翰·霍普金斯大学的资源中心。

PROJECT SUMMARY/ABSTRACT Annually, about 50,000,000 doses of synthetic gadolinium imaging contrast agents are injected into patients worldwide when getting an MRI. While these agents are extremely safe, they have the potential for adverse effects in some patients. Also, they may accumulate in brain and bone tissues when a procedure is repeated, with yet unknown risks. Currently, all MRI agents require some kind of chemical labeling, i.e. with para- or ferro-magnetic metals or, recently, with hyperpolarized magnetic isotopes. The overall goal of this BRG is the development of simple D-glucose as an MRI contrast agent. Advantages of using such a natural agent are safety, absence of interference with contrast on standard anatomical images, low cost, and the ability to perform repeated studies over a short period of time. We will first develop this technology for brain cancer, after which it can be adjusted for general use. Contrast agents are used to visualize tumor anatomy and physiology, which can provide information on malignancy and the response to treatment. Our hypothesis is that D-glucose as an infusible MRI contrast agent can provide information on three important aspects of tumor physiology, namely delivery, uptake (including effects of blood brain barrier disruption), and metabolism. If our developments are successful, translation to clinical application will be fast since D-glucose is already widely used for other indications (e.g. glucose tolerance test for diabetes), and its safety profile is well established. Our preliminary data show MRI detectability of D-glucose at millimolar concentrations in animal models at 11.7T and in brain tumor patients at 7T and 3T. However, there are technical issues at 3T due to the reduced effect size, requiring additional technology development for motion correction, data acquisition, and analysis. Our overall development goal for this BRG is to optimize and standardize the use of D-glucose as an infusible contrast agent for diagnostic and prognostic imaging of tumor physiology at the clinical field strength of 3T. The specific aims are (1) Design and optimize fast whole-brain dynamic MRI saturation pulse sequence technology to detect D-glucose based (a) T2 relaxation effects, (b) combined chemical exchange saturation transfer (CEST) and T2 relaxation effects; (2) Design and optimize CEST-MRI-compatible motion correction methods for dynamic scanning including navigator echo guidance and deep learning analysis; (3) Design and optimize semi-quantitative and quantitative data analysis approaches for visualizing tumor enhancement and obtaining indicators of tumor D-glucose delivery, uptake, and metabolism; (4) Standardize the methods of aims 1-3 and demonstrate repeatability and reproducibility to conclude the work with a clinical MRI protocol for dynamic glucose-enhanced (DGE) MRI. To accomplish these aims with optimal efficiency, proper validation and clinical relevance, we have established a multidisciplinary team of experts in the fields of MRI physics (pulse sequence development), clinical oncology, biostatistics, and endocrinology, which will employ the facilities of several Resource Centers available at Kennedy Krieger Institute and Johns Hopkins University.