Focused ultrasound-mediated drug delivery through the blood–brain barrier

Abstract

Despite recent advances in blood–brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents.

Keywords:

• blood–brain barrier
• drug delivery
• focused ultrasound
• neurodegenerative disease

Financial & competing interests disclosure

K Hynynen has served as an inventor on patents owned by BWH and patent applications owned by SRI. K Hynynen also has stock ownership in and has received funding from FUS instruments for pre-clinical work. 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.

Key issues

• The blood–brain barrier (BBB) in healthy individuals functions to protect the brain from harmful agents and bacteria but has also posed a major obstacle to drug delivery into the brain, preventing the treatment of neurological damage and neurodegenerative diseases.

• Almost all pharmaceuticals developed to treat neurological conditions are too large to pass through the BBB in therapeutic concentrations and it has been difficult for methods developed to circumvent the BBB (such as carrier proteins and intranasal delivery) to deliver therapeutic amounts of drug.

• Focused ultrasound (FUS) is a noninvasive method where ultrasound is used to transiently open the BBB in highly targeted brain regions and has been shown to deliver therapeutic amounts of drugs of varying sizes to these regions in preclinical models.

• Combining low-power ultrasound with the delivery of intravenous preformed microbubble contrast agent causes mechanical stimulation of the blood vessel through stable cavitation when the microbubbles encounter the ultrasound field, leading to transient, reproducible BBB opening.

• The degree of FUS-mediated BBB opening can be affected by the frequency (and therefore the pressure) of transmitted ultrasound, duration of the ultrasound pulse, pulse repetition frequency and microbubble size and dose.

• Advantages of the use of MRIgFUS for BBB opening include the elimination of the need for invasive surgery for drug delivery to the brain, precise targeting of brain regions for treatment using MRI and transient opening absent of long-term deficits in barrier function.

• Obstacles in the way of widespread clinical adoption of FUS include questions surrounding the repeatability of the FUS procedure, unknowns about the full impact of the treatment on the target and off-target brain tissue and the current dependence of the technology on MRI and a specially trained operator.

• FUS has been shown to be safe in preclinical models, with safety translating to human patient trials if the further development of the clinical transducers integrates safety measures, such as the real-time acoustic feedback controller, which allows the operator to monitor and control the FUS treatment.

• Clinical translation of MRIgFUS for treatment of brain tumors within the next 5 years is essential for moving MRIgFUS toward widespread clinical adoption.

Notes