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

D-葡萄糖作为癌症 MRI 诊断剂的开发和转化

• 批准号: 10732247
• 负责人: Linda Knutsson
• 金额: $ 66.47万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732247
• 关键词: Address; Adverse effects; Affect; Anatomy; Animal Model; Biometry; Blood Vessels; Bone Tissue; Brain; Brain Neoplasms; Brain imaging; Chemicals; Clinic; Clinical; Clinical Oncology; Collaborations; Computer software; Contrast Media; Data; Data Analyses; Detection; Development; Diabetes Mellitus; Diagnostic; Disease; Dose; Endocrinology; Gadolinium; Glucose; Glucose tolerance test; Goals; Healthcare; Image; Industry; Infusion procedures; Intravenous; Isotopes; Kidney Diseases; Label; Leadership; Legal patent; Licensing; MRI Scans; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Malignant neoplasm of brain; Manufacturer; Metabolism; Metals; Methodology; Methods; Modernization; Monitor; Motion; Outcome; Patients; Performance; Perfusion; Physics; Physiologic pulse; Physiology; Play; Population; Predisposition; Procedures; Process; Protocols documentation; Relaxation; Reporting; Reproducibility; Research; Resource Sharing; Resources; Risk; Role; Running; Safety; Scanning; Sensitivity and Specificity; Signal Transduction; Standardization; Technology; Therapeutic; Time; Tissues; Toxic effect; Translating; Translations; Universities; Validation; Visualization; Water; Work; anatomic imaging; blood-brain barrier disruption; blood-brain barrier permeabilization; brain tissue; cancer imaging; clinical application; clinical translation; clinically relevant; computerized data processing; contrast enhanced; contrast imaging; cost; data acquisition; deep learning; design; experience; extracellular; glucose transport; multidisciplinary; noninvasive diagnosis; patient population; prognostic; psychologic; side effect; statistics; sugar; technology development; timeline; treatment response; tumor; uptake

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.

项目概要/摘要 每年大约有 50,000,000 剂量的合成钆成像造影剂被注入 全世界的患者在接受 MRI 检查时。虽然这些药物非常安全，但它们有潜力 对某些患者产生不良反应。此外，当手术进行时，它们可能会积聚在大脑和骨组织中。 重复，但风险未知。目前，所有 MRI 试剂都需要某种化学标记，即 顺磁性或铁磁性金属，或者最近使用超极化磁性同位素。本次活动的总体目标 BRG 是开发简单的 D-葡萄糖作为 MRI 造影剂。使用这种天然材料的优点 试剂安全、不干扰标准解剖图像的对比度、成本低、 在短时间内进行重复研究的能力。我们首先会为大脑开发这项技术 癌症，之后可以调整为一般用途。造影剂用于可视化肿瘤解剖结构 和生理学，可以提供有关恶性肿瘤和治疗反应的信息。我们的假设是 D-葡萄糖作为不溶性 MRI 造影剂可以提供肿瘤三个重要方面的信息 生理学，即输送、摄取（包括血脑屏障破坏的影响）和新陈代谢。如果我们的 开发成功，由于 D-葡萄糖已经广泛应用，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），其安全性已得到充分证实。 我们的初步数据显示 MRI 可检测动物模型中毫摩尔浓度的 D-葡萄糖 11.7T，脑肿瘤患者为7T和3T。然而，由于 3T 的减少，存在技术问题 效应大小，需要额外的技术开发来进行运动校正、数据采集和分析。 我们对该 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 用于在 3T 临床场强下对肿瘤生理学进行诊断和预后成像的造影剂。这 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 检测基于 D-葡萄糖的 (a) T2 弛豫效应，(b) 组合化学交换饱和转移 (CEST) 和 T2 松弛效应； (2)设计并优化CEST-MRI兼容的运动校正方法 用于动态扫描，包括导航回波引导和深度学习分析； (3)设计与优化 用于可视化肿瘤增强并获得的半定量和定量数据分析方法 肿瘤D-葡萄糖输送、摄取和代谢指标； (4) 标准化目标1-3的方法和 展示可重复性和再现性，以通过临床 MRI 协议完成动态工作 葡萄糖增强 (DGE) MRI。为了以最佳效率、适当的验证和临床来实现这些目标 相关性，我们建立了 MRI 物理（脉冲序列）领域的多学科专家团队 开发）、临床肿瘤学、生物统计学和内分泌学，这将利用多个机构的设施 肯尼迪克里格研究所和约翰霍普金斯大学设有资源中心。