Using ultrasound to enhance targeted radiotherapy

The use of radiation as a selective modality for the treatment of cancer and various other diseases is a fundamental principle in modern medicine. However, despite decades of research and development, selective internal radiation therapy (SIRT), the arterial delivery of radioactive particles for the treatment of hepatic tumours, remains a poorly utilised technology outside of the liver. A major challenge for SIRT is the current lack of control over the distribution of particles in the affected tissue. Achieving a uniform distribution throughout the tumour mass is critical for ensuring a therapeutically relevant dose of radiation and hence successful treatment. Cavitation of microbubbles has been successfully employed to facilitate the extravasation of various nanoparticles and therapeutic agents in tissue. It is hypothesised that ultrasound induced cavitation has the potential to move larger micron sized particles used within SIRT, to increase the distribution of the therapeutic microspheres. The primary goal of this doctoral thesis is to investigate the potential use of ultrasound-induced cavitation to enhance SIRT by facilitating transport of radioactive microspheres in tissue.
A secondary goal of the thesis is to explore its use in the treatment of other types of cancer, in particular Glioblastoma Multiforme; a particularly grave cancer of high incidence. First, a tissue phantom and experimental protocol are designed to enable observation of the transport of microspheres induced by ultrasound exposure using high resolution X-ray computed tomography (µCT) imaging. Proof of concept results are obtained to confirm the feasibility of the approach. An analysis framework and image processing software are then employed to enable quantification of microsphere transport in three dimensions and the corresponding radiation exposure that could be achieved. A detailed investigation of the parameter space is then made using a statistical Design-of-Experiments methodology to identify the conditions under which a suitable microsphere distribution can be achieved; peak negative pressure correlated non-linearly with post focal projection depth and could be used to make predictions with 88.4% confidence for 95% of the observations used in the model. Finally, ultra-high speed imaging (0.1-2Mfps) is used to explore the mechanisms by which cavitation promotes microsphere transport; producing novel brightfield images of microbubble cloud activity and mass transport of dense glass microspheres. Overall, the results presented in the thesis demonstrate the feasibility of using ultrasound induced cavitation to enhance SIRT within target tissues not readily treated by an arterial route. Further work to understand the impact of tissue heterogeneity and the design of a bespoke ultrasound transducer will be required to enable clinical translation.

Keywords: radiation
microparticles
radioembolic
HIFU
intraoperative therapy
ultrasound
cavitation
glioblastoma
radiotherapy
GBM
cavitation nuclei
acoustic radiation
cancer
cloud cavitation
SIRT
adjuvant therapy
microbubbles
medical device
tissue phantom
high-speed imaging
Advisor: Stride, E
Lewis, A