Xenon-based Molecular Sensors in Analytical Applications

The development of xenon-based molecular sensors over the past decade has traditionally pointed toward applications in clinical diagnostics, with an emphasis on targeted molecular imaging using molecular sensors as a switchable contrast agent. While this would be a tremendous boon to medical physics, the potential for xenon-based MR contrast agents in analytical applications should not be understated. The phenomenal chemical shift range of xenon, dependent both on its chemical as well as its physical environment, coupled with its solubility and hyperpolarizability, makes xenon an excellent candidate for extracting information about a system of interest using NMR on optically opaque, unrefined samples./nTo effectively use xenon-based molecular sensors in analytical applications, several changes are necessary to typical experimental protocols. To optimize the detection of xenon in samples containing little analyte, modifications to the Hyper-CEST detection scheme are employed to improve magnetization transfer while simultaneously controlling more precisely the saturation bandwidth and power. These saturation sequences, demonstrated here as a series of d-SNOB shaped pulses, are used in both imaging and spectroscopic modalities, the latter enabling detection of extremely low concentrations of contrast agent./nXenon-based analysis of biological materials depends on understanding the interactions between the contrast agents, a modified cryptophane cage, and lipids. The interaction of such contrast agents with lipid suspensions is characterized, including the response of both a Xeaq signal and a Xe@cage signal to the lipid concentration, as well as discernible changes in both signals as a result of temperature changes. Furthermore, the selective detection of Xe@cageaq and Xe@cagelipid is demonstrated in both spectroscopic and imaging modes./nIn addition, the general temperature response of xenon-based molecular sensors in aqueous solutions is characterized. Because the Hyper-CEST detection scheme relies on exchange of xenon with the contrast agent, controlling the flux through the agent dramatically affects the signal. At increased temperatures (37-40 °C), analyte can be detected at concentrations much lower than is possible at room temperature. Also, the frequency dependence of the MR signal on temperature is characterized, with the response of xenon in a molecular sensor approximately ten-fold greater than xenon without a molecular sensor, and even more sensitive than the temperature response of protons--the temperature of a sample can be monitored with a resolution of approximately 0.5 K with this approach./nLastly, the development of a molecular sensor scaffold, termed MS2CA and constructed by conjugating over 100 copies of a cryptophane cage to the interior of a viral capsid, enables dramatically enhanced sensitivity when working with xenon-based contrast agents. By employing the techniques described above, including optimized saturation transfer methods and elevated temperature, MS2CA contrast agents can be detected at 700 fM--far less agent than when using most other MR contrast agents. Furthermore, the MS2CA scaffold allows for increased solubility of the contrast agent in aqueous solutions. The sensitivity limit of this contrast agent is sufficient to detect even trace compounds in a mixture./nThe incorporation of all of these developments in xenon-based molecular sensing may lead to integrated MR devices, capable of screening for bulk physiochemical properties of a sample, rather than the identification of unique compounds. Such devices may potentially be miniaturized and operated a low magnetic fields, further increasing the availability and affordability of such analysis using magnetic resonance.

Advisor: Pines, Alexander