Add the ability to associate a single xenon nucleus with a specific molecular target, for example a protein or sugar on the surface of a cancer cell. To do this, the Pines and Wemmer labs have created biosensors equipped with cages that take up and hold onto xenon atoms; the cages, molecules called cryptophanes, are linked to ligands that target specific molecules of interest. Xenon biosensors engineered with several different ligands can be used at the same time; once in place, biosensors carrying hyperpolarized xenon can localize the MRI signals from a range of different molecules on the target.

The final advance underlying the new technique is called Hyper-CEST: hyperpolarized xenon chemical-exchange saturation transfer. While biosensors can bring the xenon to specific molecular targets, in realistic applications relatively few of these are present, only about one percent compared to the total amount of free xenon injected near that target. The signal from the polarized xenon inside the biosensor cages is consequently much fainter than that from the uncaged polarized xenon nearby.

The trick then is to depolarize the xenon nuclei in the immediate vicinity of the cages, which will serve to outline the target in high contrast against the surrounding hyperpolarized xenon pool. This is done through chemical exchange, as xenon atoms are constantly entering and leaving the biosensor cages.

A polarized xenon atom from the pool enters the cryptophane cage, which alters the xenon's resonance frequency, allowing it to be depolarized by rf radiation tuned to a specific frequency. The depolarized xenon atom is then exchanged for a new, incoming polarized atom and reenters the pool. In this way the buildup of nearby depolarized nuclei quickly outlines the target.

Because it produces a much stronger signal, Hyper-CEST acquires images thousands of times faster than would imaging the caged xenon directly. Yet it retains the great advantages of cryptophane biosensors, including their ability to "multiplex," or detect different targets at the same time.

"Slight differences in cage composition, involving only a carbon atom or two, affect the frequency of the signal from the xenon and produce distinct peaks in the NMR spectrum," says team member Tyler Meldrum, of the Materials Sciences Division. "If we design different cages for different xenon frequencies, we can put them all in at once and, by selectively tuning the rf pulses, see peaks at the frequencies corresponding to each kind of cage."

More Industry Headlines