Acoustic Cluster Therapy (ACT) — pre-clinical proof of principle for local drug delivery and enhanced uptake

Abstract

Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30 µm large bubbles in the microvasculature, occluding blood flow for ~ 5-10 min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g. released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co-administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery.

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

“…Regular, free flowing microbubbles are typically moving and at a distance, whereas the ACT bubbles are for a period in constant close contact with the endothelium over a significant segment [21]. Furthermore, regular microbubbles are typically cleared from the vasculature 2-3 minutes after injection, whereas ACT bubbles deposits and stay for 5-10 minutes [22]. Also, we postulate that ACT, in addition to regular microbubble mechanisms, could influence the pressure gradient between the vascular compartment and the interstitium.…”

“…The experimental set up was as previously described [22]. In brief, for activation (Activation US) of the microbubble-microdroplets, the tumor was insonated by regular diagnostic US using a clinical VScan system (GE Healthcare AS, Oslo, Norway), with a transducer center frequency of 2.25 MHz and nominal mechanical index (MI) of 0.8 (Peak Negative Pressure, PNP, of 1.2 MPa).…”

“…In our previous papers [20][21][22] we have described the basics of the ACT formulation and concept, shown the attributes of the large, activated bubbles in-vivo, and provided proof of principle for targeted, tumor specific uptake. In the current paper, we demonstrate proof of concept for this new treatment strategy by evaluating synergistic effects from combining ACT with paclitaxel and nab-paclitaxel (Abraxane®) for treatment of human prostate adenocarcinoma in mice.…”

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

“…Details of the ACT formulation concept are described previously 22-24. In brief, the ACT formulation is produced by electrostatic complexation between negatively charged microbubbles and positively charged oil microdroplets.…”

Primary Porcine Brain Endothelial Cells as In Vitro Model to Study Effects of Ultrasound and Microbubbles on Blood–Brain Barrier Function

“…Consequently, it is important to tune the US exposure to find the optimal US frequency, peak negative pressure and duty cycle to obtain sufficient opening allowing nanoparticles and drugs to enter the brain tissue without causing permanent disruption of the BBB, hemorrhage, or functional damages [6], [9]. In addition, new generations of microbubbles acting as drug carriers are being developed [13]- [15]. In order to work within the safety window of the FUS exposure using various microbubbles, fine tuning of the US parameters to obtain efficient drug delivery without tissue damage has to be performed [16].…”