Ultrasound-Mediated Blood–Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies

Abstract

Ultrasound-mediated blood–brain barrier (BBB) disruption has garnered focus as a method of delivering normally impenetrable drugs into the brain. Numerous studies have investigated this approach, and a diverse set of ultrasound parameters appear to influence the efficacy and safety of this approach. An understanding of these findings is essential for safe and reproducible BBB disruption, as well as in identifying the limitations and gaps for further advancement of this drug delivery approach. We aimed to collate and summarise protocols and parameters for achieving ultrasound-mediated BBB disruption in animal and clinical studies, as well as the efficacy and safety methods and outcomes associated with each. A systematic search of electronic databases helped in identifying relevant, included studies. Reference lists of included studies were further screened to identify supplemental studies for inclusion. In total, 107 articles were included in this review, and the following parameters were identified as influencing efficacy and safety outcomes: microbubbles, transducer frequency, peak-negative pressure, pulse characteristics, and the dosing of ultrasound applications. Current protocols and parameters achieving ultrasound-mediated BBB disruption, as well as their associated efficacy and safety outcomes, are identified and summarised. Greater standardisation of protocols and parameters in future preclinical and clinical studies is required to inform robust clinical translation.

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

“…Since its first description in the 1940s, significant improvements have been made in altering ultrasound parameters to reduce the potential of induced tissue damage, and in developing non- or minimally invasive delivery methods of ultrasound [ 53 ]. Given the relative safety, availability, low costs, and high efficacy of ultrasound technology, ultrasound-mediated BBB opening has become a hot topic in brain drug delivery [ 54 ]. Recent developments in ultrasound techniques such as MR-guided focused ultrasound (MRgFUS) and Transcranial Pulse Stimulation (TPS) have provided a unique toolbox to potentially overcome some of the limitations of brain cancer therapies.…”

“…The magnitude and spatial extent of BBB opening, as well as the safety of this approach, depends on several ultrasound parameters, including transducer type, pressure amplitude, sonication time, transducer frequency, geometry of the transducer and number of sonication points, pulse characteristics (pulse length and pulse repetition frequency) as well as MB-related parameters [ 163 , 198 , 199 ]. A recent systematic review of such parameters and their effects on the extent and safety of BBB opening across pre-clinical and clinical studies was conducted by Gandhi et al [ 54 ]. Using appropriate parameters, therapeutic agents ranging from low-molecular-weight drugs [ 59 , 200 , 201 , 202 ], larger molecular weight molecules such as monoclonal antibodies [ 139 , 203 ], gene vectors (both non-viral and viral) [ 204 , 205 , 206 ] and nanoparticles to even stem cells [ 207 ] and natural killer cells [ 208 ], have been successfully delivered to brain cancer sites in pre-clinical studies.…”

“…Ultrasound-induced BBB opening in small-to-large animal models has been used to study enhanced delivery of a variety of chemotherapeutic agents [ 54 , 202 ] such as herceptin [ 139 ], liposomal doxorubicin [ 52 ], cytarabine [ 224 ], doxorubicin [ 200 ], temozolomide [ 225 ], and methotrexate [ 226 ], as well as genes [ 227 , 228 , 229 , 230 ], viruses [ 228 ], and cells [ 207 ]. This concept, as well as relevant animal models, chemotherapeutic drugs, and the acoustic parameters used for BBB opening, have been recently reviewed [ 54 , 126 , 202 ]. Beyond BBB modification, ultrasound sonication has shown significant beneficial effects for several other neurological diseases, including seizure and epilepsy, in non-human primates [ 231 , 232 , 233 , 234 ].…”

Influence of Acoustic Parameters and Sonication Schemes on Transcranial Blood–Brain Barrier Disruption Induced by Pulsed Weakly Focused Ultrasound

“…This threelayered structure forms a barrier to protect the brain from circulating toxic molecules. Normally only lipophilic molecules smaller than 500 Da can pass through the BBB [1][2][3][4][5][6][7][8][9][10]. Although this barrier is efficient for brain protection, it limits therapeutic molecules to enter the brain for disease treatment.…”

“…Strategies to overcome the BBB includes intraventricular injection, convection enhanced delivery, carotid artery injection of hyperosmolar solution, and intranasal delivery to cerebrospinal fluid. These approaches are too invasive or results in only limited drug diffusion [6,9,10,12,13]. Some strategies modify drugs by drug lipidization, protein cationization, or chimeric peptide technology to enhance their BBB permeability, but therapeutic applications of these agents are under limited development [14].…”