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

 描述(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的解剖和生理，这可以提供关于恶性肿瘤和治疗反应的信息。目前，所有有用的磁共振造影剂都需要某种类型的化学标记，即用顺磁性金属标记，或者最近用超极化磁性同位素标记。在此，我们建议开发简单的D-葡萄糖作为MRI造影剂。我们将通过使用葡萄糖上的羟基质子作为天然磁性标记来实现这一点，该标记可以使用专门设计的一系列射频(RF)脉冲来激活。这种标签被转移到水中，可以使用标准的MRI硬件进行检测。使用适当剂量的天然制剂(如D-葡萄糖)的一些优点是安全、不干扰标准解剖图像的对比、低成本以及能够在短时间内进行重复研究。我们的假设是，D-葡萄糖可以作为一种不熔化的MRI造影剂，提供有关肿瘤生理的两个重要方面的信息，即灌注率和通透性。我们预计，由于D-葡萄糖已经被广泛用于其他适应症，如糖尿病的葡萄糖耐量试验，而且它的安全性已经确立，因此转化为临床应用将是快速的。我们最近获得的初步数据显示，在模体、动物模型和第一例脑肿瘤患者中，D-葡萄糖在毫摩尔浓度的MRI可检测到。我们的总体目标是开发D-葡萄糖作为一种不溶的MRI造影剂用于肿瘤血流和渗透性的联合成像，并将其应用于临床。因此，我们制定了工程、生化和临床目标，以(I)设计和优化通过模体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脉冲序列方法学转换为人类扫描仪，(Iii)设计数据分析方法和软件包，以可视化肿瘤增强并获得肿瘤灌注和通透性的生理指标，(Iv)研究造影剂的机制，(V)首先在7T和随后的3T证明D-葡萄糖作为脑肿瘤患者的MRI造影剂的适用性，(Vi)为了优化和标准化可重复静脉D-葡萄糖成像的临床MRI方案，为了以最佳的效率和适当的验证来实现这一目标，并确保临床实用性，我们提议建立一个由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的专家组成的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.