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Abstract

Cases of radio-recurrent prostate cancer (PCa) are difficult to treat effectively and would benefit from the advancement of non-invasive, image-guided alternative therapies. Therapeutic ultrasound is a minimally or non-invasive method of tissue ablation. Thermal therapeutic ultrasound can be used to necrose tissue via heat deposition, while mechanical ultrasound ablation, or histotripsy, induces liquefaction of tissue through violent bubble cloud activity. Both thermal and mechanical ultrasound ablation have been applied to treatment of prostate tissue, but with limited therapeutic efficacy. Ultrasound exposure can be used to non-invasively improve the uptake and distribution of therapeutics, and can act on sonodynamic therapy (SDT) agents to generate cytotoxic reactive oxygen species (ROS). The combination of therapeutic ultrasound with therapeutic agents may improve treatment outcomes in radio-recurrent PCa patients. Clinical translation of therapeutic ultrasound is also limited by the image-guidance methods currently available. Improved imaging metrics are needed to better plan, treat, and evaluate thermal ultrasound ablation and histotripsy, as well as to quantify the release of drugs or generation of ROS during SDT. The first aim of this dissertation examined a novel theranostic nanoparticle for improved image guidance and therapeutic efficacy in thermal ultrasound ablation of the prostate. This particle’s capacity for accelerating ultrasound-induced heating, delivery of a therapeutic payload, and magnetic resonance (MR) image contrast were explored. This dissertation’s second aim evaluated multi-modal image guidance methods for histotripsy therapy using agarose phantom, porcine liver, and human blood clot models. The ability of several diagnostic ultrasound and MR image modalities to assess liquefaction of phantoms or tissue was evaluated. Finally, the third aim of this dissertation explored the use of histotripsy to generate sonochemical reactions for SDT. In addition to quantifying the amount of ROS produced by histotripsy exposure with and without sonosensitizing agents, passive cavitation imaging (PCI) was tested as a quantitative dose metric for SDT. The theranostic nanoparticle explored in Aim 1 was found to enhance heating, but did not adequately release its contrast payload, indicating limited utility as an MR contrast agent or drug-delivery vehicle. The particle did not confound guidance and evaluation of the therapy with MR imaging. The second aim of this dissertation showed PCI to best predict the location of sample liquefaction, whereas MR imaging provided the most accurate delineation of the ablation zone. MR imaging parameters exhibited more drastic changes following liquefaction of tissue compared with agarose phantom. The third aim of this thesis demonstrated that ROS production increased with the peak negative pressure of ultrasound exposures, and scaled linearly with the acoustic power measured via PCI. Exposure of titanium dioxide (TiO2) nanoparticles to histotripsy did not significantly increase the amount of cavitation emissions observed or the quantity of ROS produced, suggesting limited efficacy of histotripsy in sonoactivation of TiO2. The studies carried out in this thesis have indicated several potential improvements of therapeutic efficacy and image guidance in therapeutic ultrasound and sonodynamic therapy. These contributions may help facilitate the clinical translation of therapeutic ultrasound technologies for treatment of PCa and other pathologies.

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