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

描述(申请人提供)：实体肿瘤的特征是酸性和缺氧的微环境，以及混乱和泄漏的微血管。癌症的这些特征与不良的临床结果、肿瘤复发和转移的可能性以及对治疗的抵抗有关。生物医学成像手段以最小或零侵袭性询问肿瘤微环境的这些特征，对于抗击这种疾病至关重要，因为它们提供了预测结果和跟踪对传统和实验性抗癌治疗的反应的潜力。这项申请提出了一种开发磁共振成像(MRI)造影剂的策略，该造影剂在体内可逆地结合到循环白蛋白上。通过调节这些Gd络合物与白蛋白的亲和力，人们在特定的目标1中建议开发造影剂，这种造影剂将以一种依赖于局部组织氧化还原状态的方式增强MRI图像。这一点很重要，因为肿瘤中的缺氧区与高浓度的还原物种有关。在MRI图像上，增强含有高浓度还原物种的肿瘤区域的能力将是评估肿瘤低氧的一种非侵入性手段。在特定目标2中，我们建议利用这些络合物与白蛋白的结合亲和力来生产倾向于保留在血管内的MRI造影剂(血池造影剂)。白蛋白结合的Gd在高血管渗透性肿瘤区域的渗出将在MRI图像上突出显示这些区域。这一点很重要，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)的高水平表达有关，血管内皮生长因子是一种强大的血管生成分子。在MRI图像上突出肿瘤泄漏区域的能力将是识别肿瘤中活跃的血管生成区域的一种非侵入性手段。持续清除未结合的Gd池将最大限度地减少与过长的体内寿命相关的毒性。在AIMS 1和2中开发的氧化还原敏感性和血池造影剂将与肿瘤缺氧和血管内皮生长因子表达的组织学分析进行验证。这项应用的总体目标是开发具有重要病理特征的肿瘤磁共振成像生物臂，以帮助选择和非侵入性地跟踪靶向治疗。

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.