Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: Safety and efficacy evaluation in rhesus macaques

  • McDannold N
  • Arvanitis C
  • Vykhodtseva N
 et al. 
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Abstract

The blood-brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarilypermeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% was found to be half of the value that would produce tissue damage. Acoustic emission measurements appeared promising for predicting BBB disruption and damage. In addition, we performed repeated BBB disruption to central visual field targets over several weeks in animals trained to perform complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings demonstrate that BBB disruption can be reliably and repeatedly produced without evident histological or functional damage in a clinically-relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive targeted drug delivery method.

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