In this project, we will develop new gadolinium-based contrast agents that are exquisitely sensitive to pH and establish their feasibility in determining extracellular pH in vivo using a standard clinical MRI protocol. Extracellular pH is clearly an important parameter to know in neoplastic tissues because it has been shown that acidosis can modulate the cytotoxicity of some anticancer drugs, influence thermal radio-sensitization and enhance the killing effects of heat. We recently demonstrated that a simple gadolinium complex containing a single, slowly exchanging, inner-sphere water molecule senses pH via catalytic exchange of bound water protons. This unique chemical feature offers a major advantage over other known gadolinium complexes because proton relaxivity is not limited by molecular exchange of the bound water. This means that complexes with water relaxivity values higher than previously achieved can be made by attaching existing small molecule pH sensitive agent to polymers of increasing size. We have licensed this technology from the University of Texas at Dallas and through the current funding mechanism intend to create even more pH responsive MRI agents, demonstrate their utility in vivo in animal models, and make them commercially to the biomedical research community.
Magnetic resonance imaging is widely used to detect tumors in humans, yet little physiological information is gained in a normal MRI exam. We plan to develop new pH sensitive contrast agents that can be safely injected into patients to determine the extracellular pH of tumors using a standard imaging protocol. We believe this could become a standard protopcol in clinical oncology.
| Woods, Mark; Kiefer, Garry E; Bott, Simon et al. (2004) Synthesis, relaxometric and photophysical properties of a new pH-responsive MRI contrast agent: the effect of other ligating groups on dissociation of a p-nitrophenolic pendant arm. J Am Chem Soc 126:9248-56 |
