Focused ultrasound-mediated enhancement of blood-brain barrier permeability for brain tumor treatment: a systematic review of clinical trials

Abstract

Purpose: Brain tumors, particularly glioblastoma multiforme (GBM), present significant prognostic challenges despite multimodal therapies, including surgical resection, chemotherapy, and radiotherapy. One major obstacle is the limited drug delivery across the blood-brain barrier (BBB). Focused ultrasound (FUS) combined with systemically administered microbubbles has emerged as a non-invasive, targeted, and reversible approach to transiently open the BBB, thus enhancing drug delivery. This review examines clinical trials employing BBB opening techniques to optimise pharmacotherapy for brain tumors, evaluates current challenges, and proposes directions for further research.

Methods: A systematic literature search was conducted in PubMed and ClinicalTrials.gov up to November 2023, searching for "ultrasound" AND "brain tumor". The search yielded 1446 results. After screening by title and abstract, followed by full-text screening (n = 48), 35 studies were included in the analysis.

Results: Our analysis includes data from 11 published studies and 24 ongoing trials. The predominant focus of these studies is on glioma, including GMB and astrocytoma. One paper investigated brain metastasis from breast cancer. Evidence indicates that FUS facilitates BBB opening and enhances drug uptake following sonication. Exploration of FUS in the pediatric population is limited, with no published studies and only three ongoing trials dedicated to this demographic.

Conclusion: FUS is a promising strategy to safely disrupt the BBB, enabling precise and non-invasive lesion targeting, and enhance drug delivery. However, pharmacokinetic studies are required to quantitatively assess improvements in drug uptake. Most studies are phase I clinical trials, and long-term follow-up investigating patient outcomes is essential to evaluate the clinical benefit of this treatment approach. Further studies involving diverse populations and pathologies will be beneficial.

Keywords: Blood-brain barrier; Brain tumor; Focused ultrasound; Glioblastoma; Microbubbles.

Fig. 1

Schematic of FUS-Induced BBB Disruption. The application of ultrasound waves to targeted brain region induces microbubble-seeded acoustic cavitation. This process generates intravascular shear stress, leading to reversible changes in BBB permeability, thereby facilitating the enhanced penetration of therapeutic agents into brain tissue. Adapted from “Lipid-Based Microbubbles (MBs) as Ultrasound-Based Drug Delivery System” by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates

Fig. 2

PRISMA flow chart illustrating the identification and selection process