Hyperpolarized C-13 Magnetic Resonance Imaging for Assessing Tissue Metabolism and Microenvironment: Technical Development, Preclinical Validation, and Clinical Translation

Hyperpolarized (HP) C-13 magnetic resonance (MR) is an emerging molecular imaging technique that has shown the potential to assess metabolic and microenvironmental alterations in various diseases. MR spectroscopic imaging methods can monitor the distribution and biochemical conversion of injected HP C-13 labeled probes. These quantitative imaging markers could address the unmet clinical needs of non-invasive evaluation of cancer aggressiveness, disease burden, and early therapeutic response or resistance. This dissertation focuses on developing HP C-13 MR probes and techniques to evaluate cellular redox capacity, glycolytic metabolism, as well as tissue perfusion and microenvironment. Chapter 1 introduces the fundamental principles of MR, hyperpolarization techniques, and their biological and clinical applications. Chapter 2 describes using ascorbate-derived MR and Positron Emission Tomography probes to interrogate in vivo redox capacity of the brain. Chapter 3 reports the preclinical validation of the combined HP C-13 pyruvate and urea MR as a simultaneous metabolic and perfusion imaging technique to evaluate early and dose-dependent tumor response to radiation therapy in a prostate cancer mouse model. The results of Chapter 3, combined with other prior preclinical evidence, motivated the clinical translation of this dual-probe imaging technique. Chapter 4 describes the technical development (including co-polarization system development, probe characterizations, and imaging methodology development) and non-clinical studies (including impurity characterizations, toxicology study, and imaging feasibility study) required to translate the combined C-13 pyruvate and urea MR for clinical investigations. This work has led to the regulatory approval of this combined metabolic and perfusion imaging technique for investigational use to aid prostate cancer diagnosis in patients