Production And NMR Characterization Of Dynamic Nuclear Polarization-Enhanced Yttrium-89 Complexes And Carbon-13 Organic Compounds



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Nuclear magnetic resonance (NMR) is a phenomenon that describes the microscopic environment of nuclear spins under the external magnetic field by applying radiofrequency waves at their corresponding nuclear Larmor frequency, and widely used in materials science, biochemistry, and medical imaging. It allows one to investigate molecular structural information and dipolar intramolecular interactions noninvasively. However, the majority of the nuclei are insensitive to NMR spectrometer and exhibit minute NMR signals due to their intrinsic weak nuclear magnetic moments. This low signal-to-noise issue has been mitigated by an approach called dynamic nuclear polarization (DNP) in which the high polarization of electron spins is transferred to the nuclei via microwave irradiation close to electron Larmor frequency at high magnetic field and low temperature. To harness this enhanced NMR signal for biomedical or chemical applications, the dissolution process is employed wherein the frozen polarized nuclei samples are rapidly dissolved into hyperpolarized liquids at physiological temperatures. Using this technology, the NMR signals of weak nuclei such as 13C and 89Y can be enhanced by several thousand-fold relative to their thermal equilibrium NMR signals. The bulk of this PhD dissertation entails a discussion of the details of DNP physics and applications of hyperpolarized low-gamma nuclei such as 13C-enriched organic compounds and 89Y-complexes that have chemical and biological relevance. Furthermore, this thesis also involves a discussion the construction of a homebuilt cryogen-free and variable-field DNP instrumentation. This DNP instrumentation is a major leap in the field of hyperpolarization since it does not require expensive liquid helium for DNP operation. As such, this instrumentation allowed us to measure, for the first time, the solid-state T1 relaxation times of 13C compounds at 1.8 K in the 0-9 T magnetic field range. The main finding of this measurement is that the 13C T1 relaxation times of carboxylates follow a power law dependence on magnetic field according to T1~B2-3 at cryogenic temperature. Meanwhile, the feasibility of hyperpolarized 89Y-EDTMP and 89Y-DTPMP as potential chemical shift-based NMR sensors for pH was studied. The results of this study show that hyperpolarized 89Y-EDTMP has a relatively wide chemical shift range of 16 ppm over pH 5-9 range with pKa close to neutral—a promising pH sensor for future in vivo applications. In addition, dissolution DNP also allows one to track the complexation of free Y3+ ion and ligand such as DOTA in realtime under certain buffered solution conditions, giving insight as a model for Gd3+ complexation with specific macrocyclic ligands. Furthermore, dissociation of 89Y-DTPA into free 89Y ion and DTPA ligand in the presence of Zn2+ in the solution has been monitored in real-time, providing a direct chemical reaction monitoring process for the complex. Additionally, the effect of 13C nuclear spin density of 13C DNP signal and T1 relaxation was also investigated. Finally, this thesis also includes a 13C/15N NMR investigation of alanine metabolism in glioblastoma cells. In summary, this PhD dissertation encompasses a discussion of the analytical power of hyperpolarized and conventional NMR spectroscopy in the investigation of chemical and biological systems.



Nuclear magnetic resonance, Nuclear magnetic resonance spectroscopy, Yttrium