Focused Ultrasound Preconditioning for Augmented Nanoparticle Penetration and Efficacy in the Central Nervous System.
Authors: Mead BP, Curley CT, Kim N, Negron K, Garrison WJ, Song J, Rao D, Miller GW, Mandell JW, Purow BW, Suk JS, Hanes J, Price RJ
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 K<sub>trans</sub> 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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether focused ultrasound (FUS) pre-conditioning can enhance the distribution and transgene expression of systemically delivered brain-penetrating gene-vector nanoparticles across the blood–brain barrier.
Animal model / Human subject
rat, Sprague–Dawley, 8–12 weeks, male
Disease model
healthy
Targeted brain region(s)
Striatum
Cargo name and characteristics
Gene-vector 'brain-penetrating' nanoparticles — nanoparticle-based gene vectors delivering genetic material for transgene expression
Route of administration
intravenous
Outcomes and Safety
Summary of Outcomes
Activation of microbubbles with 1 MHz focused ultrasound (FUS) sequences increased the volume of transfected brain tissue after convection-enhanced delivery and, when used as FUS pre-conditioning before trans‑BBB nanoparticle delivery, produced up to a 5-fold increase in transgene expression; MRI (temperature and Ktrans) indicated these gains result from parenchymal modulation by FUS.
Duration of biological effect
28 days
Safety-related matter
No adverse effects or safety concerns were reported in the provided text; MRI analyses of tissue temperature and Ktrans were performed but no harmful effects were mentioned.
Brain Region
Ultrasound Parameters
Ultrasound instrument
single-element focused ultrasound transducer
FUS Frequency
1 MHz
FUS Intensity
not reported
FUS Pressure
not reported
FUS Mode
not reported
Pulse duration
not reported
Duration of a single FUS session
not reported
Treatment frequency
single
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