Towards standardization of the parameters for opening the blood-brain barrier with focused ultrasound to treat glioblastoma multiforme: A systematic review of the devices, animal models, and therapeutic compounds used in rodent tumor models.
Authors: Thombre R, Mess G, Kempski Leadingham KM, Kapoor S, Hersh A, Acord M, Kaovasia T, Theodore N, Tyler B, Manbachi A
Glioblastoma multiforme (GBM) is a deadly and aggressive malignant brain cancer that is highly resistant to treatments. A particular challenge of treatment is caused by the blood-brain barrier (BBB), the relatively impermeable vasculature of the brain. The BBB prevents large molecules from entering the brain parenchyma. This protective characteristic of the BBB, however, also limits the delivery of therapeutic drugs for the treatment of brain tumors. To address this limitation, focused ultrasound (FUS) has been safely utilized to create transient openings in the BBB, allowing various high molecular weight drugs access to the brain. We performed a systematic review summarizing current research on treatment of GBMs using FUS-mediated BBB openings in <i>in vivo</i> mouse and rat models. The studies gathered here highlight how the treatment paradigm can allow for increased brain and tumor perfusion of drugs including chemotherapeutics, immunotherapeutics, gene therapeutics, nanoparticles, and more. Given the promising results detailed here, the aim of this review is to detail the commonly used parameters for FUS to open the BBB in rodent GBM models.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To systematically review and analyze focused ultrasound (FUS) treatment parameters used to open the blood–brain barrier in rodent glioblastoma models to identify optimal indicators for BBB permeabilization.
Animal model / Human subject
Rodents (mice and rats); strain not specified; age not specified; sex not specified
Disease model
Glioblastoma multiforme (GBM)
Cargo name and characteristics
Various therapeutic cargos including chemotherapeutics (small-molecule drugs), immunotherapeutics (proteins/antibodies), gene therapeutics (viral vectors such as AAV and plasmid-based gene delivery), and nanoparticles
Outcomes and Safety
Summary of Outcomes
Focused ultrasound with microbubbles transiently opened the blood–brain barrier in rodent GBM models, increasing tumor uptake of chemotherapies, immunotherapies, gene/nanoparticle therapies and improving tumor control/survival; successful parameters reported included ~1 MHz frequency, peak-negative pressure ~0.6–0.8 MPa (openings reported down to 0.12 MPa), ~1% duty cycle, ~10 ms burst length, ~1–2 min total sonication per spot, and microbubble dose ≈0.1 mL/kg.
Safety-related matter
FUS-mediated BBB opening is described as a safe, noninvasive, and transient method in rodent GBM models—thermal effects are negligible at commonly used parameters and repeated openings reportedly do not cause long-term BBB damage. However, the review cautions that exceeding recommended acoustic pressures, long burst lengths, or inappropriate microbubble dosing can cause unstable/inertial cavitation and tissue damage, and histological safety outcomes were inconsistently reported across studies.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
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