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Small. 2019 Dec;15(49):e1903460. doi: 10.1002/smll.201903460. Epub 2019 Oct 22.

Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System.

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Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, USA.
Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, 22908, USA.
Department of Pathology, University of Virginia, Charlottesville, VA, 22908, USA.
Department of Neurology, University of Virginia, Charlottesville, VA, 22908, USA.


Microbubble activation with focused ultrasound (FUS) facilitates the noninvasive and spatially-targeted delivery of systemically administered therapeutics across the blood-brain barrier (BBB). FUS also augments the penetration of nanoscale therapeutics through brain tissue; however, this secondary effect has not been leveraged. Here, 1 MHz FUS sequences that increase the volume of transfected brain tissue after convection-enhanced delivery of gene-vector "brain-penetrating" nanoparticles were first identified. Next, FUS preconditioning is applied prior to trans-BBB nanoparticle delivery, yielding up to a fivefold increase in subsequent transgene expression. Magnetic resonance imaging (MRI) analyses of tissue temperature and Ktrans confirm that augmented transfection occurs through modulation of parenchymal tissue with FUS. FUS preconditioning represents a simple and effective strategy for markedly improving the efficacy of gene vector nanoparticles in the central nervous system.


focused ultrasound; microbubbles; nanoparticles; nonviral gene delivery


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