Magnetic resonance imaging of oxygen nano-carriers for the treatment of hypoxic tumours

In cancer therapy, tumour hypoxia is an important predictor of disease progression, treatment outcomes, and metastatic potential. To date, methods for reducing tumour hypoxia have delivered limited success owing to either a lack of proven efficacy, unwanted side effects, or logistical limitations. Therefore, there remains an urgent requirement for an effective hypoxia reduction mechanism that is safe, cost effective, biocompatible, and easy to use. To address this, oxygen-filled micro and nanobubbles have been investigated as a method of oxygen delivery and have shown promising results in improving therapeutic response. To develop and optimise oxygen carriers and other hypoxia reduction strategies, however, consistent methods for measuring changes in tissue oxygenation need to be established. The ideal method should be noninvasive and quantitative, allowing tumour oxygen measurements to be obtained before, during, and after treatment. This thesis examines whether clinically available MRI techniques can be used to detect the change in tissue oxygenation caused by the nano-carriers. A combination of phantom and preclinical experiments, mathematical modelling, and the analysis of data from two clinical trials are used. First, original results from phantom and preliminary in vivo MRI experiments are reported, which demonstrate the feasibility of detecting the effects of oxygen carriers. Second, three separate mathematical models are developed and presented in order of increasing complexity 2 first addressing simple bodily fluids, then blood, and finally, tissues 2 each of which are useful for areas of MRI research beyond the focus of this thesis. Third, original research results from recently completed clinical studies of oxygen-enhanced MRI are analysed and used to assess the viability of using these MRI measurements to monitor oxygen delivery from nanobubbles in a clinical MRI setting. Lastly, the broader potential applications of the conclusions and tools presented in this thesis are discussed.