The Effects of Ultrasound on Convection-Enhanced Delivery

Abstract

Neurological diseases such as glioblastoma multiforme are difficult to treat because the blood-brain barrier prevents most therapeutic drugs administered through the bloodstream from entering the brain. One way of overcoming this is by infusing the drug directly into the diseased site in the brain using either a needle or a cannula, a technique known as convection-enhanced delivery (CED). CED uses a pressure gradient to disperse the drug farther than if the drug were dispersed solely by diffusion. However, once the drug has been injected into the brain, physicians lose the ability to control the spatial distribution of the drug. Ultrasound focused via time-reversal acoustics (TRA) has been shown to further increase the distribution volume of CED infusions, raising the possibility that TRA-focused ultrasound may be used to direct the distribution of substances infused into brain tissue. In this dissertation, ultrasound focused adjacent to the infusion site did not appear to affect the distribution of Evans blue–labeled bovine serum albumin (EBA) in 0.2% wt/vol agarose gels or in vivo in the caudate putamen of rodent brains. Ultrasound focused at the site of infusion did not affect the distribution volumes of tracers when they were co-infused with microbubbles, but did significantly increase the distribution volume of EBA when it was co-infused with 20-nm, but not 40-nm, polystyrene particles. Results from a diffusion model suggest that ultrasound may have enhanced the convective phase rather than the diffusive phase of these infusions. Examination of rodent brain sections using fluorescence microscopy showed a distribution of EBA interspersed with regions of low Evans blue intensity that coincided with axon bundles, suggesting that the distribution of substances in the caudate putamen is not uniform even within seemingly homogeneous grey matter. This may partially account for the disappointing results from advanced CED clinical trials so far.