Surg-04. influence of low-intensity focused ultrasound on locoregional drug delivery to the brain

Abstract INTRODUCTION Efficient delivery of therapeutic drugs across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Among the different approaches developed to circumvent these limitations to improve drug delivery to a target tissue, low-intensity focused-ultrasound (LIFU) is a particularly appealing strategy as it will transiently disrupt the blood-brain barrier. Locoregional (intrathecal [IT] and convection-enhanced delivery [CED]) are clinically relevant routes of drug delivery that bypass the BBB and avoid systemic exposure. These routes of administration are known to achieve otherwise unobtainable drug concentration in specified target tissue. However, it remains unknown how locoregional routes of delivery coupled with FUS could change the drug targeting and pharmacokinetics. METHODS In the present study, we quantitatively assessed how FUS coupled with IT, IV, or CED altered fluorescent dye (Dextran 2000kD) distribution and concentration in a predetermined neurotomical region in a naïve murine model. We then analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye. RESULTS Our results indicate that IV administration coupled with LIFU will successfully cause diffusion of dye into the pre-defined sonication targets. Alternatively, measurable dye in the sonication target was hardly detected when administered IT in comparison to IV delivery (VIT = 1.25mm3; VIV = 36.20mm3). In addition, our preliminary qualitative analysis suggests that LIFU coupled with CED shows shorter time of residence of the dye in the parenchyma when compared to CED alone. This suggests that increased BBB permeability from FUS leads to faster drug clearance. CONCLUSION Our results highlight the distributive and pharmacokinetic influence of FUS on various locoregional drug delivery routes.