Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood–Brain Tumour Barrier

Abstract

Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic agents to treat tumours; however, most approaches have several limitations which hinder their clinical utility. Promising studies indicate that ultrasound can penetrate the skull to target specific brain regions and transiently open the BBB, safely and reversibly, with a high degree of spatial and temporal specificity. In this review, we initially describe the basics of therapeutic ultrasound, then detail ultrasound-based drug delivery strategies to the brain and the mechanisms by which ultrasound can improve brain tumour therapy. We review pre-clinical and clinical findings from ultrasound-mediated BBB opening and drug delivery studies and outline current therapeutic ultrasound devices and technologies designed for this purpose.

Nanoparticle-Based Combinational Strategies for Overcoming the Blood-Brain Barrier and Blood-Tumor Barrier

“… 115 , 116 The use of ultrasound in combination with NPs has been shown to further enhance the delivery of therapeutic agents to the brain, as NPs can act as carriers for the drugs and facilitate their transport across the disrupted BBB. 115 , 117 , 118 Low-frequency focused ultrasound (FUS) is an innovative and non-invasive approach for temporarily and reversibly opening the BBB. This strategy, guided by magnetic resonance imaging (MRIgFUS), uses low-frequency ultrasound waves in concert with gas-filled microbubbles (MBs) to specifically disrupt the BBB.…”

“…Another challenge is ensuring that the therapeutic agents are delivered specifically to the tumor site and not to healthy brain tissue, which could cause neurological damage. 117 , 118 …”

“…Additionally, research is ongoing to investigate the use of ultrasound-mediated drug delivery in combination with other strategies, such as immunotherapy, to enhance the therapeutic efficacy of glioblastoma treatment. 116 , 118 …”

“…The depth of penetration of the magnetic field into brain tissue is limited, which may limit its effectiveness for deeper brain regions. 118 In addition, the use of high-intensity magnetic fields raises concerns about potential tissue heating and damage, posing a risk to patient safety. 138 , 139 Therefore, while magnetic field strategies represent a promising avenue for crossing the BBB, their application must be carefully balanced with these inherent limitations.…”

State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound

“…In addition, MB-assisted focused-US can also alter the gene expression of essential BBB efflux transport proteins, such as downregulation of the P-glycoprotein, which enhances medication localization in the parenchyma (Aryal et al 2017, Jangjou et al 2021, Conti et al 2022. However, it is difficult to understand the precise mechanism of interactions between MB and tissues leading to BBB disruption (Barzegar-Fallah et al 2022).…”