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Theranostics 2017; 7(1):144-152. doi:10.7150/thno.15987 This issue Cite

Research Paper

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

Kang-Ho Song^1,2, Alexander C. Fan^1,2, Joshua J. Hinkle², Joshua Newman², Mark A. Borden^1✉, Brandon K. Harvey^2✉

1. Department of Mechanical Engineering, University of Colorado, Boulder, CO 80309.
2. Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224.

✉ Corresponding authors: Mark A Borden, PhD., Department of Mechanical Engineering, University of Colorado, 1111 Engineering Drive, Boulder, CO 80309-0427. Phone: 303.492.7750; Fax: 303.492.3498; Email: mark.bordenedu or Brandon K. Harvey, Ph.D., Director, Optogenetics and Transgenic Technology Core, Associate Scientist, Glia-Neuron Interactions Unit, National Institute on Drug Abuse, Biomedical Research Building, Suite 200, Room 06A729, 251 Bayview Blvd, Baltimore, MD 21224. Phone: 443-740-2590 (office); Email: bharveynih.gov. More

Abstract

Focused ultrasound with microbubbles is being developed to transiently, locally and noninvasively open the blood-brain barrier (BBB) for improved pharmaceutical delivery. Prior work has demonstrated that, for a given concentration dose, microbubble size affects both the intravascular circulation persistence and extent of BBB opening. When matched to gas volume dose, however, the circulation half-life was found to be independent of microbubble size. In order to determine whether this holds true for BBB opening as well, we independently measured the effects of microbubble size (2 vs. 6 µm diameter) and concentration, covering a range of overlapping gas volume doses (1-40 µL/kg). We first demonstrated precise targeting and a linear dose-response of Evans Blue dye extravasation to the rat striatum for a set of constant microbubble and ultrasound parameters. We found that dye extravasation increased linearly with gas volume dose, with data points from both microbubble sizes collapsing to a single line. A linear trend was observed for both the initial sonication (R²=0.90) and a second sonication on the contralateral side (R²=0.68). Based on these results, we conclude that microbubble gas volume dose, not size, determines the extent of BBB opening by focused ultrasound (1 MHz, ~0.5 MPa at the focus). This result may simplify planning for focused ultrasound treatments by constraining the protocol to a single microbubble parameter - gas volume dose - which gives equivalent results for varying size distributions. Finally, using optimal parameters determined for Evan Blue, we demonstrated gene delivery and expression using a viral vector, dsAAV1-CMV-EGFP, one week after BBB disruption, which allowed us to qualitatively evaluate neuronal health.

Keywords: ultrasound contrast agent, drug delivery, gene therapy, pharmacokinetics.

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