Improved Drug Distribution using Rapid Short-Pulse (RaSP) Sequences In Vivo to Open the Blood-Brain Barrier

One third of the worldwide disease burden – number of years lost due to disease – is caused by brain diseases, such as dementia, Parkinson’s and brain cancer (DiLuca and Olesen 2014). With an aging population, this burden is expected to rise. Despite the global effort to develop new treatments, there are still no effective drugs for these diseases. One of the major reasons for the lack of successful therapies is that the majority of drugs cannot enter the brain due to the bloodbrain barrier (BBB) (Lu et al 2014). A promising solution to this problem is the use of focused ultrasound and microbubbles to locally and noninvasively open the BBB so that therapeutic agents can enter the brain (Hynynen et al 2001). Since its inception, ultrasound technology has been shown to deliver a range of drugs across the BBB (Burgess et al 2015). However, several underlying factors, such as concerns of efficacy and safety, have prevented its clinical translation in human patients (Baseri et al 2010, Choi et al 2007, Pouliopoulos et al 2016). We have previously shown that current ultrasound technology produces a poor drug distribution and damages arteries (Choi et al 2010). This efficacy-safety limit is likely a result of the use of conventional ultrasound pulse shapes and sequences, which have poor control over cavitation dynamics, generating a mixture of desired and undesired cavitation activity (Choi and Coussios 2012). We have recently developed and tested a new low pressure rapid short-pulse (RaSP) sequence in vitro, designed to promote the desired cavitation activity in the correct location (Pouliopoulos et al 2016). This new sequence will be evaluated here for its ability to improve the efficacy and safety of ultrasound-mediated drug delivery to the brain in vivo.