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

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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether Acoustic Cluster Therapy (ACT) can safely and effectively open the blood-brain barrier in rats to enhance delivery of small and large model drugs using lower ultrasound pressures than conventional microbubbles.

Animal model / Human subject Mouse (Mus musculus); strain not stated; age not stated; sex not stated

Disease model Healthy

Cargo name and characteristics Abraxane® — albumin‑bound paclitaxel nanoparticle; additionally the study reports delivery of unspecified small molecules and larger macromolecules into the brain

Outcomes and Safety

Summary of Outcomes Acoustic Cluster Therapy (ACT) with focused ultrasound transiently and safely opened the BBB, markedly increasing delivery of small (gadodiamide) and large (~45 kDa IRDye‑PEG) molecules with only mild, infrequent focal microhemorrhages. The most effective ultrasound regimen was ACT with the phase‑shift activation step plus a 10‑minute low‑MI enhancement step (ACT+A+E); ACT+activation (A) gave moderate opening, ACT+enhancement (E) alone and saline controls were ineffective, and these effects were achieved at acoustic power ~5–10× lower than conventional microbubble protocols.

Duration of biological effect 10 min

Safety-related matter The authors report that ACT safely and transiently permeabilized the BBB using lower ultrasound pressures and, by histology, showed no signs of eosinophilic neuronal degeneration, gliosis, inflammation, microglial/macrophage reaction, and generally no hemorrhage; however, the ACT+A+E group exhibited a few focal microhemorrhages that were scored as mild and of no clinical relevance.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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