Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection.

Abstract

The delivery of systemically administered gene therapies to brain tumors is exceptionally difficult because of the blood-brain barrier (BBB) and blood-tumor barrier (BTB). In addition, the adhesive and nanoporous tumor extracellular matrix hinders therapeutic dispersion. We first developed the use of magnetic resonance image (MRI)-guided focused ultrasound (FUS) and microbubbles as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered "brain-penetrating" nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with "per voxel" flow directions changing by an average of ~70° to 80°. Last, we observed that FUS-mediated BTB/BBB opening increased the dispersion of directly injected BPNs through tumor tissue by >100%. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.