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. ? ? ?
