Focal disruption of the blood–brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery

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  • Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston; and Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Object

The goal of this study was to explore the feasibility of using low-frequency magnetic resonance (MR) image–guided focused ultrasound as a noninvasive method for the temporary disruption of the blood–brain barrier (BBB) at targeted locations.

Methods

Rabbits were placed inside a clinical 1.5-tesla MR imaging unit, and sites in their brains were targeted for 20-second burst sonications (frequency 260 kHz). The peak pressure amplitude during the burst varied between 0.1 and 0.9 MPa. Each sonication was performed after an intravenous injection of an ultrasound contrast agent (Optison). The disruption of the BBB was evaluated with the aid of an injection of an MR imaging contrast agent (MAG-NEVIST). Additional tests involving the use of MION-47, a 20-nm magnetic nanoparticle contrast agent, were also performed. The animals were killed at different time points between 3 minutes and 5 weeks postsonication, after which light or electron microscopic evaluation was performed.

The threshold for BBB disruption was approximately 0.2 MPa. More than 80% of the brain sites sonicated showed BBB disruption when the pressure amplitude was 0.3 MPa; at 0.4 MPa, this percentage was greater than 90%. Tissue necrosis, ischemia, and apoptosis were not found in tissue in which the pressure amplitude was less than 0.4 MPa; however, in a few areas of brain tissue erythrocytes were identified outside blood vessels following exposures of 0.4 MPa or higher. Survival experiments did not show any long-term adverse events.

Conclusions

These results demonstrate that low-frequency ultrasound bursts can induce local, reversible disruption of the BBB without undesired long-term effects. This technique offers a potential noninvasive method for targeted drug delivery in the brain aided by a relatively simple low-frequency device.

Abbreviations used in this paper: BBB = blood-brain barrier; EC = endothelial cell; HMW = high molecular weight; HRP = horseradish peroxidase; MR = magnetic resonance; SD = standard deviation; TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling.

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Contributor Notes

Address reprint requests to: Kullervo Hynynen, Ph.D., Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Room S6 65B, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. email: khynynen@sri.utoronto.ca.
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