Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection.
Authors: Curley CT, Mead BP, Negron K, Kim N, Garrison WJ, Miller GW, Kingsmore KM, Thim EA, Song J, Munson JM, Klibanov AL, Suk JS, Hanes J, Price RJ
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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To determine whether MRI-guided focused ultrasound with microbubbles can enhance delivery and intratumoral dispersion of systemically administered brain-penetrating gene nanoparticle vectors by opening the blood–brain/tumor barriers and altering interstitial tumor flow.
Animal model / Human subject
Athymic nude mice (U87, U87mCherry tumors); 6-8 weeks; male; C57BL/6 mice (B16F1ova tumors); 8-10 weeks
Disease model
Glioblastoma; brain metastasis (melanoma)
MRI or image guidance method
MRI-guided (magnetic resonance imaging)
Targeted brain region(s)
Brain Tumor And Surrounding Tissue
Cargo name and characteristics
Brain-penetrating nanoparticle (BPN) gene vectors — nanoparticle-based gene therapy vectors/nanocarriers (systemically administered gene delivery nanoparticles)
Route of administration
Intravenous (systemically administered) and intratumoral (directly injected)
Outcomes and Safety
Summary of Outcomes
MRI-guided 1‑MHz focused ultrasound (FUS) with microbubbles markedly increased delivery and transfection of systemically administered ~50 nm brain-penetrating gene nanoparticles into U87 and B16F1ova brain tumors, accompanied by increased intersitial fluid velocity and altered flow direction, and enhanced intratumoral dispersion and transfection volume
Safety-related matter
No adverse effects were reported: FUS + microbubbles at the tested pressures (0.45 and 0.55 MPa) did not elicit detectable inertial cavitation or signs of tissue damage, and prior related studies found no histological damage or overt gliosis at similar or higher pressures.
Brain Region
Ultrasound Parameters
Ultrasound instrument
MRI-guided FUS system (RK-100, FUS Instruments); 1.1 MHz spherically focused single-element transducer
FUS Frequency
1.1 MHz
FUS Pressure
0.45 Mpa
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
2 minutes
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
Single
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