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Remote Detection of Xenon-based Molecular Sensors and the Development of Novel Paramagnetic Agents


Applications of laser-polarized xenon nuclear magnetic resonance (NMR) spectroscopy and imaging have grown in number due to the exceptional sensitivity of xenon to its local environment. When paired with microfluidic technology, xenon-based molecular sensors (XBMS) have the potential to be used in a broad range of applications from medical devices to geochemistry. Detection of XBMS on a microfluidic chip requires remote detection NMR methodology, where the encoding and detection of aqueous xenon is separated in both space and time. In order to give a clear sense for the state of XBMS with respect to both microfluidics in NMR and magnetic resonance (MR) contrast agents, this thesis provides the background of NMR relevant for performing remote detection NMR experiments, a history of laser-polarized xenon NMR spectroscopy, traditional proton-based magnetic resonance (MR) contrast agents, and the development of XBMS as MR contrast agents.

The primary XBMS used in this thesis is a water soluble version of the organic cryptophane-A molecule (cryA). Xenon had been shown to associate with cryA in water with high affinity and relatively fast exchange and cryA can be indirectly detected in low concentrations in solution. A variable previously unexploited in laser-polarized xenon NMR experiments using XBMS was temperature. Temperature is an important parameter in XBMS experiments for generating MR contrast as the affinity for xenon with all soluble versions of cryptophane-A had been shown to increase with increasing temperature and also the exchange of xenon in and out of the cryA was previously shown to increase at higher temperatures. In experiments described in this thesis, temperature was used to increase contrast in both spectroscopic and imaging studies. At 37 C, the threshold for detecting the presence of a negatively charged cryA in solution was decreased to 10 nM - two orders of magnitude lower than what was previously detectable for a positively charged cryA at 25 C.

In order to detect the presence of XBMS with an optimized coil separated in space from the location of the sensors (remote detection), a radio frequency (RF) probe tuned to the resonance of xenon was built that was compatible with aqueous xenon flow through 1/16 inch tubing. An efficient means of dissolving xenon into water close to the encoding region was developed leading to the detection of the first aqueous xenon remote detection travel curves. Furthermore, polystyrene beads grafted with 1.3 mM cryA were loaded into 1/16 inch tubing in the encoding region. By applying a saturation pulse at the cryA resonance frequency in the encoding region, the presence of cryA was remotely detected by monitoring the subsequent decrease in intensity at the aqueous xenon resonance frequency.

Following the remote detection of XBMS in this macroscopic environment, a platform was developed for the remote detection of XMBS on a microfluidic chip. An RF probe tuned to both H-1 and Xe-129 was designed and fabricated for remote detection experiments at the microfluidic scale. This probe was used to detect aqueous xenon flowing through a microfluidic chip via the time-of-flight dimension. Furthermore, water proton flow through a microfluidic chip was detected in remotely in both spectroscopic and imaging experiments.

Finally, a novel class of XBMS is discussed in detail. Instead of detecting XBMS by their unique resonance frequency in solution, when paired with a paramagnetic center XBMS have the potential to be used as T1 relaxation agents. The theory of T1 contrast agents is presented and the simulation developed to model this new type of xenon-based contrast agent is described in detail. The results of the simulation are tabulated and the early work with the first agent synthesized for this purpose is presented. The incorporation of a XBMS T1 relaxation agent with a microfluidic device could lead to the development of chemically sensitive, portable, low-field devices.

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