Redox-Sensitive & Blood-pool Contrast Agents for Magnetic Resonance Imaging

氧化还原敏感

• 批准号: 7477727
• 负责人: NATARAJAN RAGHUNAND
• 金额: $ 20.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477727
• 关键词: Affinity; Albumins; Angiogenic Factor; Area; Binding; Biodistribution; Biological Assay; Biological Markers; Blood; Blood Tests; Blood Vessels; Characteristics; Clinical; Complex; Condition; Contrast Media; Data; Disease; Dose; Drug Kinetics; EF5; Extravasation; Gadolinium; Goals; Human; Hypoxia; Image; Image Enhancement; Invasive; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measures; Methods; Microvascular Permeability; Modality; Motion; Mus; Neoplasm Metastasis; Outcome; Oxidation-Reduction; Performance; Population; Property; Protons; Rate; Recurrence; Refractory; Renal clearance function; Serum Albumin; Solid Neoplasm; Staining method; Stains; Standards of Weights and Measures; Structure; Sulfhydryl Compounds; Testing; Tissues; Toxic effect; Vascular Endothelial Growth Factors; Vascular Permeabilities; Water; bioimaging; cancer therapy; design; disulfide bond; fight against; gadoteridol; improved; in vitro Assay; in vivo; response; small molecule; therapy resistant; tumor; uptake

DESCRIPTION (provided by applicant): Solid tumors are characterized by an acidic and hypoxic microenvironment, and a disorganized and leaky microvasculature. These characteristics of cancers are associated with adverse clinical outcomes, likelihood of tumor recurrence and metastasis, and resistance to therapies. Biomedical imaging modalities to interrogate these features of the tumor microenvironment with minimal or no invasiveness are crucial to the fight against this disease, as they offer the potential for predicting outcome and following response to conventional and experimental anti-cancer therapies. This application proposes a strategy for developing contrast agents for Magnetic Resonance Imaging (MRI) which bind reversibly to circulating albumin in vivo. By modulating the affinity of these complexes of gadolinium for albumin, it is proposed in Specific Aim 1 to develop contrast agents which will enhance MRI images in a manner dependent on the local tissue redox status. This is significant because hypoxic regions in tumors hav e been associated with high concentrations of reducing species. The ability to enhance, on MRI images, tumor regions with high concentrations of reducing species would be a non-invasive means of assessing tumor hypoxi a. In Specific Aim 2, we propose to exploit the binding affinity of these complexes for albumin to produce MRI contrast agents which tend to remain intravascular ("blood-pool" contrast agents). Extravasation of albumin-bound gadolinium in tumor regions of high vascular permeability will highlight such areas on MRI images. This is significant because tumor regions with high microvascular permeability (leakiness) are associated with high levels of expression of Vascular Endothelial Growth Factor (VEGF), a potent angiogenic molecule. The ability to highlight leaky regions in tumors on MRI images would be a non-invasive means to identify actively angiogenic regions in a tumor. Continuous clearance of the unbound pool of gadolinium will minimize toxicity associated with excessively long in vivo lifetimes of the gadolinium. The redox-sensitive and blood-pool contrast agents developed in aims 1 and 2 will be validated against histological assays of tumor hypoxia and VEGF expression. The overall goal of this application is to develop Magnetic Resonance Iaging biomarm kers of pathologically significant characteristics of tumors, to aid in the selection of, and non-invasively follow response to, targeted therapies.

描述（由申请人提供）：实体瘤的特征是酸性和缺氧微环境，以及紊乱和渗漏的微血管。癌症的这些特征与不良临床结果、肿瘤复发和转移的可能性以及对治疗的抗性相关。以最小或无侵入性来询问肿瘤微环境的这些特征的生物医学成像模式对于对抗这种疾病至关重要，因为它们提供了预测结果和跟踪对传统和实验性抗癌疗法的反应的潜力。本申请提出了一种用于开发用于磁共振成像（MRI）的造影剂的策略，所述造影剂在体内可逆地结合循环白蛋白。通过调节钆的这些络合物对白蛋白的亲和力，在具体目标1中提出开发造影剂，其将以依赖于局部组织氧化还原状态的方式增强MRI图像。这是重要的，因为肿瘤中的缺氧区域与高浓度的还原物质相关。在MRI图像上增强具有高浓度还原物质的肿瘤区域的能力将是评估肿瘤缺氧的非侵入性方法。在特定目标2中，我们提出利用这些复合物对白蛋白的结合亲和力来生产倾向于保持在血管内的MRI造影剂（“血池”造影剂）。白蛋白结合钆在高血管渗透性肿瘤区域的外渗将在MRI图像上突出显示这些区域。这是重要的，因为具有高微血管渗透性（渗漏）的肿瘤区域与血管内皮生长因子（VEGF）（一种有效的血管生成分子）的高水平表达相关。在MRI图像上突出显示肿瘤中的渗漏区域的能力将是识别肿瘤中活跃的血管生成区域的非侵入性手段。连续清除未结合的钆池将使与钆的体内寿命过长相关的毒性最小化。将针对肿瘤缺氧和VEGF表达的组织学测定来验证在目标1和2中开发的氧化还原敏感性和血池造影剂。本申请的总体目标是开发具有肿瘤病理学显著特征的磁共振成像生物标记物，以帮助选择靶向治疗，并无创跟踪对靶向治疗的反应。