The goal of this project is to develop ¹²⁹Xe MRI biosensors for early cancer detection, and possible therapeutic intervention. Xenon binds more tightly within cryptophanes (K_d ~10^-4 M) than other organic cages, making cryptophanes attractive for xenon imaging experiments. Xenon gas is sensitive to its molecular environment, and small perturbations near the cryptophane produce large changes in the ¹²⁹Xe NMR chemical shift.  Moreover, xenon is biologically compatible, diffuses readily in vivo, and can be “hyperpolarized” to enhance the NMR signal 10,000-fold. These properties form the basis for a sensitive imaging reagent capable of simultaneously monitoring multiple analytes in vivo, each causing a unique ¹²⁹Xe chemical shift. This “multiplexing” capability offers unparalleled opportunities for molecular imaging of tumorigenesis, where simultaneous identification of multiple cancer markers would speed diagnosis, and improve treatment. Two particularly challenging, but important goals are the early detection of pancreatic and brain cancers, as these neoplasms are a leading cause of cancer death in the U.S., and their regulation is poorly understood at the molecular level. 

We are currently synthesizing cryptophanes and other carriers that will have greater affinity for xenon, longer ¹²⁹Xe hyperpolarized spin-lattice relaxation times, and unique chemical shifts. ¹²⁹Xe*cryptophane binding is characterized by NMR studies and X-ray crystallography.  We are attaching targeting agents and will soon demonstrate specific delivery to cancer cells in tissue culture.  An “arsenal” of cryptophanes and other imaging reagents will be evaluated for their deliverability, tumor selectivity, marker specificity, and ¹²⁹Xe signal intensity. ¹²⁹Xe MRI results will be validated using fluorescently labeled carriers and subsequently imaging tissue in vivo and ex vivo: such “ground truthing” will help to evaluate the diagnostic accuracy of this new technology.  Overall, this work is focused on the detection of multiple biomarkers for the early diagnosis of breast, pancreatic, and brain cancers.  Xenon hyperpolarization capabilities have recently been developed in the lab to facilitate many biological studies.