Localized delivery of non-viral gene-bearing nanoparticles into the rat brain following focused ultrasound-mediated BBB opening

Background/introduction By preventing more than 98% of currently used pharamaceutical agents from entering the brain, the blood-brain barrier critically reduces the ability of therapeutics to treat a variety of central nervous system (CNS) disorders including glioblastoma and neurodegenerative diseases. Focused ultrasound (FUS) mediated microbubble oscillation and subsequent blood brain barrier (BBB) permeabilization has been explored as a powerful non-invasive strategy for the delivery of circulating therapeutic agents into the CNS. FUS in conjunction with microbubbles has been shown to facilitate non-damaging, reversible and localized disruption of the BBB, leading to substantial increases in nanoparticle (NP) concentrations in ultrasound-treated tissue. Once beyond the BBB, the extracellular matrix acts as a steric and adhesive barrier and limits NP distribution. Coating sub-100 nm nanoparticles with a dense brush layer of polyethylene glycol (PEG) to limit the interactions with the ECM leads to a significant improvement of their diffusivity in brain tissue. The current study investigates the ability of FUS to deliver densely PEGylated brain penetrating cationic polymerbased gene vectors across the BBB to mediate robust and long-term transgene expression.