Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability

ABSTRACT

Introduction: Treatment of several diseases of the brain are complicated by the presence of the skull and the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubble (MB)-mediated BBB treatment is a minimally invasive method to transiently increase the permeability of blood vessels in targeted brain areas. It can be used as a general delivery system to increase the concentration of therapeutic agents in the brain parenchyma.

Areas covered: Over the past two decades, the safety of using FUS+MBs to deliver agents across the BBB has been interrogated through various methods of imaging, histology, biochemical assays, and behavior analyses. Here we provide an overview of the factors that affect the safety profile of these treatments, describe methods by which FUS+MB treatments are controlled, and discuss data that have informed the assessment of treatment risks.

Expert opinion: There remains a need to assess the risks associated with clinically relevant treatment strategies, specifically repeated FUS+MB treatments, with and without therapeutic agent delivery. Additionally, efforts to develop metrics by which FUS+MB treatments can be easily compared across studies would facilitate a more rapid consensus on the risks associated with this intervention.

Trial registration: ClinicalTrials.gov identifier: NCT03321487.

Trial registration: ClinicalTrials.gov identifier: NCT03119961.

Trial registration: ClinicalTrials.gov identifier: NCT02343991.

Trial registration: ClinicalTrials.gov identifier: NCT03608553.

Trial registration: ClinicalTrials.gov identifier: NCT03626896.

Trial registration: ClinicalTrials.gov identifier: NCT03616860.

Trial registration: ClinicalTrials.gov identifier: NCT03671889.

Trial registration: ClinicalTrials.gov identifier: NCT03712293.

KEYWORDS:

• Blood-brain barrier
• focused ultrasound
• microbubbles
• targeted drug delivery
• low intensity pulsed ultrasound
• image-guided therapy

Article highlights

• Focused ultrasound and microbubble treatment is a minimally invasive method to transiently increase blood-brain barrier permeability in targeted locations.

• For hours after sonication, therapeutic agents can be administered systemically and extravasate in targeted brain areas.

• The magnitude of increased blood-brain permeability following focused ultrasound and microbubble treatment ranges greatly between studies – largely due to differences in exposure conditions – leading to the observation of a range of biological responses following sonication.

• With appropriately selected parameters, blood-brain barrier permeability can be transiently increased without evidence of behavioral deficits, structural damage, or lasting histopathological changes; however, substantial, long-lasting damage can be induced with parameters that are suboptimal.

• Real-time acoustic feedback control has greatly increased the safety profile of focused ultrasound and microbubble treatments and continues to develop.

• Phase 1 clinical trials are underway at several institutes, with positive early results.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Dr. Ryan Jones for his help with editing and consultation on microbubble dynamics and phased arrays. Figure 1 was created with BioRender.io.

Declaration of interest

K Hynynen is an inventor on issued patents and patent applications related to transcranial focused ultrasound technology. K Hynynen owns stock in FUS Instruments, which has licensed IP related to the methods described in this review for pre-clinical use. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a founder of CarThera, a company developing an approach to disrupt the blood-brain barrier using an implantable ultrasound approach. Another reviewer on this manuscript has disclosed that they have a number of filed and issued patents related to both intranasal delivery of drugs to the brain and to focused ultrasound delivery of drugs to the brain. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

Funding for this work was provided by The National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (R01 EB003268), The Canadian Institutes for Health Research (FRN 119312), and the Canada Research Chair Program (awarded to K Hynynen).