As oncolytic treatments continue to improve and patient survival times increase, cancer cells have more and more time to metastasise from the primary tumour to other locations in the body. This is particularly dangerous when metastases spread to the brain; the sensitivity of cerebral tissue means that brain metastases often cause severe morbidity or mortality before they are large enough to detect clinically. Current treatments for this condition are palliative and woefully inadequate; their lack of targeting causes such severe side effects that many patients choose to forgo them. Originally used for clinical imaging, ultrasound is being developed as a low cost, non-invasive and non-ionising therapeutic modality. Microbubbles, originally developed as ultrasound contrast agents, are capable of encapsulating a wide range of therapeutic agents and encouraging uptake of these agents into tissue. The combination of focused ultrasound and circulating microbubbles is capable of locally and transiently permeabilising the blood brain barrier, the main obstacle to drug delivery in the brain. Chapters 2 and 3 of this thesis show that the specificity of ultrasound-mediated blood-brain barrier disruption (US-BBBD) can be increased by actively targeting microbubbles to disease sites in the brain before ultrasound exposure, removing the need for prior knowledge of the disease site. Chapters 4 and 5 of this thesis show that the efficacy of US-BBBD can be increased by optimising the lipid composition of microbubbles. This increases the delivery to in brain tissue without requiring an increase in ultrasound energy. If successfully translated to clinic, the combination of these techniques has the potential to deliver the first safe, effective and non-invasive therapy for brain metastases.
