Drug delivery across the blood-brain barrier using short-pulse focused ultrasound and microbubbles for the treatment of diffuse intrinsic pontine glioma

Abstract

The blood-brain barrier (BBB) prevents unwanted substances from entering the brain, but also blocks entry of therapeutic agents, posing difficulties for treating brain cancers such as diffuse intrinsic pontine glioma (DIPG) where surgery and therapeutic radiation are not feasible. Focused ultrasound and microbubbles can be used to increase the permeability of the BBB and deliver therapeutic substances into the brain. The NSB lab at Imperial have adapted the traditional ultrasound pulse sequences used for this technique, providing benefits to drug delivery. The aim of this PhD project is to translate the ultrasound system developed at Imperial to treat mice bearing DIPG tumours at The ICR. The thesis will reflect this journey. The introductory chapter reviews current literature and highlights the need for the ultrasound treatment for DIPG. The common methodologies chapter describes techniques used throughout the PhD project. There are three results chapters. The first describes results obtained whilst refining model drug delivery at a centre frequency of 300 kHz. The next results chapter features results obtained when refining drug delivery at the higher centre frequency of 1 MHz. The final results chapter reports the effect of delivering a therapeutic, panobinostat, to mice bearing DIPG tumours. The final chapter of the thesis provides overall conclusions of the research as well as future directions.