Selective Neuro-oncological Therapies Using Focused Ultrasound to Disrupt the Blood-brain Barrier

Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of bioeffects. Of particular interest in neuro-oncology is the interaction of ultrasound with pre-formed ultrasound contrast agents, the combination of which can be used to increase the permeability of the cerebrovasculature in a reversible manner [blood-brain barrier (BBB) disruption]. Many promising therapeutic agents have in vitro efficacy but fail in vivo due to their inability to accumulate to any significant degree in the central nervous system (CNS). While primary brain tumours alone do not impose an enormous healthcare burden compared with many other cancers, as many as 40% of all cancer patients will eventually develop brain metastasis, making the potential impact of drug delivery with ultrasound significantly larger. We focused particularly on therapeutic agents that, once in the brain, selectively targeted malignant cells, as existing therapies cause much morbidity in their wake secondary to collateral neuronal injury. We investigated the effects of BBB disruption on boron neutron capture therapy with the delivery agent boronophenylalanine. BBB disruption increased the absolute boron concentration, important for tumour killing, by almost 150%, and improved the ratio between normal brain and tumour, minimizing radiation to healthy cells. It also increased the uptake in infiltrating cells, particularly important for tumours like glioblastoma. We then demonstrated that an even more selective agent - engineered, targeted immune cells - could be delivered to a brain tumour in a viable state. Furthermore, we demonstrated improved survival in a brain metastasis model of HER2 amplified breast cancer. Both of these targeted therapies have been investigated in early clinical trials, and with the mounting evidence for the safety of BBB disruption with ultrasound, there exists real potential to translate these promising therapies into the clinical realm and offer new treatments to patients with little hope for a cure.Ph.D.2016-09-22 00:00:0