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

 描述（由申请人提供）：癌症仍然是工业化世界的主要死亡原因之一。现代成像技术使用造影剂来可视化肿瘤解剖学和生理学，这可以提供关于恶性肿瘤和对治疗的反应的信息。目前，所有有用的MRI造影剂都需要某种化学标记，即用顺磁性金属或最近用超极化磁性同位素。在这里，我们提出了简单的D-葡萄糖作为MRI造影剂的发展。我们将通过使用葡萄糖上的羟基质子作为天然磁性标签来实现这一点，该标签可以使用专门设计的一系列射频（RF）脉冲来激活。该标记转移到水中，可以使用标准MRI硬件检测。使用适当剂量的天然试剂（如D-葡萄糖）的一些优点是安全性、不干扰标准解剖图像的对比度、成本低以及能够在短时间内进行重复研究。我们的假设是，D-葡萄糖可用作可输注的MRI造影剂，提供关于肿瘤生理学的两个重要方面的信息，即灌注和渗透性。我们预计，由于D-葡萄糖已经广泛用于其他适应症，如糖尿病的葡萄糖耐量试验，并且其安全性已得到充分证实，因此将快速转化为临床应用。我们最近获得的初步数据显示，MRI检测D-葡萄糖在毫摩尔浓度的幻影，在动物模型和第一个脑肿瘤患者。我们的总体目标是开发并将D-葡萄糖作为可输注的MRI造影剂用于肿瘤灌注和渗透性的联合成像。因此，我们已经建立了工程、生物化学和临床目标，以（i）设计和优化通过体模和动物中的水信号检测D-葡萄糖所需的MRI脉冲序列技术，（ii）将MRI脉冲序列方法转化为人体扫描仪，（iii）设计数据分析方法和软件包，用于可视化肿瘤增强并获得肿瘤灌注和渗透性的生理指标，（iv）研究对比机制，（v）证明D-葡萄糖作为MRI对比剂用于脑肿瘤患者的适用性，首先在7 T，随后在3 T，和（vi）优化和标准化用于可再现静脉内D-葡萄糖成像的临床MRI方案。为了以最佳效率和适当的验证来实现这一点，并确保临床相关性，我们建议在MRI脉冲序列开发、癌症生物学、临床肿瘤学、生物统计学和内分泌学领域建立一个生物工程研究伙伴关系，该伙伴关系将利用肯尼迪克里格和约翰霍普金斯大学雨果莫泽研究所的几个资源中心的设施。

 DESCRIPTION (provided by applicant): Cancer remains one of the leading causes of death in the industrialized world. Modern imaging technologies employ contrast agents to visualize tumor anatomy and physiology, which can provide information on malignancy and the response to treatment. Currently, all useful MRI contrast agents require some kind of chemical labeling, i.e. with paramagnetic metals or, recently, with hyperpolarized magnetic isotopes. We here propose the development of simple D-glucose as an MRI contrast agent. We will accomplish this by using the hydroxyl protons on glucose as a natural magnetic label that can be activated using specially designed series of radiofrequency (RF) pulses. This label is transferred to water and can be detected using standard MRI hardware. Some of the advantages of using a natural agent such as D-glucose at an appropriate dose 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. Our hypothesis is that D-glucose can be used as an infusible MRI contrast agent that provides information on two important aspects of tumor physiology, namely perfusion and permeability. We foresee that translation to clinical application will be fast since D-glucose is already widely used for other indications, such as the glucose tolerance test for diabetes, and its safety profile is well established. We have recently acquired initial data showing the MRI detectability of D-glucose at millimolar concentrations in phantoms, in animal models and in a first brain tumor patient. Our overall goal is to develop and translate to the clinc the use of D-glucose as an infusible MRI contrast agent for the combined imaging of tumor perfusion and permeability. We therefore have established engineering, biochemical and clinical aims to (i) design and optimize the MRI pulse sequence technology needed to detect D-glucose through the water signal in phantoms and animals, (ii) to translate the MRI pulse sequence methodology to human scanners, (iii) to design data analysis approaches and software packages for visualizing tumor enhancement and obtaining physiological indicators of tumor perfusion and permeability, (iv) investigate the mechanism of contrast, (v) To demonstrate the suitability of D-glucose as an MRI contrast agent for brain tumor patients first at 7T and subsequently 3T, and (vi) To optimize and standardize a clinical MRI protocol for reproducible intravenous D- glucose imaging In order to accomplish this with optimal efficiency and proper validation and to assure clinical relevance, we propose a Bioengineering Research Partnership of experts in the fields of MRI pulse sequence development, cancer biology, clinical oncology, biostatistics, and endocrinology, which will employ the facilities of several Resource Centers available at the Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins University.