Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Timothy J. Scholl

Abstract

Glioma is the most common and aggressive primary malignant brain tumour. Glioma is typically treated with surgery followed by radio/chemotherapy. Even with aggressive treatment, median survival time is expected to be ~12 to 15 months. Reoccurrence of glioma is almost inevitable, further threatening the well-being of patients who have already endured rigorous treatment. Therefore, it is paramount to choose the most effective therapy and to accurately determine outcome as early as possible to provide optimum end-of-life care. Tumours alter their metabolism in response to increasing energy demands, mainly through increased glycolysis and accompanying lactate production. This increases production of other acids and alters intracellular and extracellular pH. Hyperpolarized 13C magnetic resonance spectroscopic imaging, is capable of measuring in vivo metabolism. Increased lactate production in tumours can be probed by imaging the metabolism of hyperpolarized [1-13C]pyruvate after injection. Similarly, extracellular pH can be mapped after measuring the concentrations of H13CO3- and 13CO2 after injection of hyperpolarized 13C bicarbonate. The objective of this thesis is to investigate molecular changes in lactate production and pH gradient in a rat glioma model. To accomplish this objective, three related projects have been undertaken. For first project, a custom-made switch-tunable radiofrequency coil was designed and constructed. This radiofrequency coil facilitated imaging 1H and 13C nuclei without any registration issues producing high signal-to-noise ratio imaging data. In the second project, C6 glioma was implanted into brains of rats, which were imaged with hyperpolarized [1-13C]pyruvate at days 7, 12, 15, 18, 21 and 24 after implantation. Between days 10 and 15, rats received one of three therapies: radiotherapy, chemotherapy, combined therapy or none. Significant early therapeutic response, measured as a reduction in the lactate-to-pyruvate ratio, was observed for effective therapy. In the final project, the same tumour model was used to study cellular pH gradient in tumours. Animals were monitored at days 8, 12 and 15 after implantation using hyperpolarized 13C bicarbonate to measure intracellular pH and a chemical exchange saturation transfer method to measure intracellular pH. Measured pH gradient in tumours showed a higher intracellular pH than extracellular pH, which was the opposite of healthy brain tissue. These studies have demonstrated the potential of hyperpolarized 13C probes to promptly measure changes in tumour metabolism. Early response assessment is important for identifying effective therapies and eliminating the toxic effects of ineffective ones. This can potentially reduce treatment costs for expensive and ineffective therapies and improve the quality of life for patients.

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