Design of MRI Contrast Agents Sensitive to Tissue Redox and Oxygen Tension

Solid tumors are characterized by low pH, hypoxia, and a chaotic and leaky vasculature. In general, these characteristics of tumors are associated with adverse clinical outcomes, resistance to radiotherapy and chemotherapies, likelihood of tumor recurrence and metastases, and shorter patient survival. Recent evidence points to the increased production of antioxidants by cells in hypoxic regions, rendering these regions of tumors highly reducing. On the one hand, a reducing extracellular milieu reduces tumor sensitivity to radiotherapy and certain platinum-based anticancer drugs. A reducing extracellular microenvironment also aids tumor cell survival and proliferation. On the other hand, drugs can and have been designed to selectively target tumor cells in reducing microenvironments. We are developing MRI contrast agents designed to be “activated” in reducing microenvironments. Our end goal is to enable targeted treatment planning through non-invasive imaging in patients with solid tumors. Utility could also extend to other pathologies such as cardiovascular disease and strokes which involve free radical formation and changes in local redox.

This work is funded by an R01 grant from the National Institutes of Health (NIH). Shown below is a molecular model of a test contrast agent molecule interacting with human serum albumin.