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. 2017 Jan 1;7(1):23-30.
doi: 10.7150/thno.16577. eCollection 2017.

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)

Andreas K O Åslund  1 , Sofie Snipstad  1 , Andrew Healey  2 , Svein Kvåle  2 , Sverre H Torp  3 , Per C Sontum  2 , Catharina de Lange Davies  1 , Annemieke van Wamel  1
Affiliations

Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)

Andreas K O Åslund et al. Theranostics. .

Abstract

The blood-brain barrier (BBB) is a major obstacle in drug delivery for diseases of the brain, and today there is no standardized route to surpass it. One technique to locally and transiently disrupt the BBB, is focused ultrasound in combination with gas-filled microbubbles. However, the microbubbles used are typically developed for ultrasound imaging, not BBB disruption. Here we describe efficient opening of the BBB using the promising novel Acoustic Cluster Therapy (ACT), that recently has been used in combination with Abraxane® to successfully treat subcutaneous tumors of human prostate adenocarcinoma in mice. ACT is based on the conjugation of microbubbles to liquid oil microdroplets through electrostatic interactions. Upon activation in an ultrasound field, the microdroplet phase transfers to form a larger bubble that transiently lodges in the microvasculature. Further insonation induces volume oscillations of the activated bubble, which in turn induce biomechanical effects that increase the permeability of the BBB. ACT was able to safely and temporarily permeabilize the BBB, using an acoustic power 5-10 times lower than applied for conventional microbubbles, and successfully deliver small and large molecules into the brain.

Keywords: Blood-brain barrier opening; acoustic cluster therapy (ACT); enhanced drug delivery; focused ultrasound.

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Conflict of interest statement

The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Treatment timeline. Grey bar indicates activation step period and black bold bar indicates enhancement step period.
Figure 2
Figure 2
Comparison of gadodiamide signal intensities from MR-images. White rings indicate BBBD, (a) ACT+A+E, (b) ACT+A, (c) Sonazoid™ +A+E. (d) Scatter plot with mean and standard deviation. ** (p<0.01), *** (p<0.001).
Figure 3
Figure 3
Extravasation of the fluorescent macromolecule IRDye 800CW-PEG to the brain after treatment with (left) ACT+A+E and (right) ACT+A.
Figure 4
Figure 4
BBBD from a representative animal. (a) Immediately after treatment, (b) 1 day after treatment and (c) 3 days after treatment. (d) Ratio of treated vs non-treated side of the brain, mean and standard deviation from 4 animals.
Figure 5
Figure 5
Histological analysis of ACT+A+E treatment. (a) T1-FLASH image showing BBB opening after treatment (magenta circle indicates treated area; magenta arrow indicates microhemorrhage). (b) HES stained image of the brain (magenta circle indicates treated area). (c) Magnified area of b showing two sites of extravasated erythrocytes (magenta arrow corresponds to the microhemorrhage in panel a, black arrow indicates small amount of extravasated erythrocytes; scale bar: 1 mm).
See this image and copyright information in PMC

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