A Harmonic Dual-Frequency Transducer for Acoustic Cluster Therapy

Acoustic Cluster Therapy (ACT) is a two-component formulation of commercially available microbubbles (Sonazoid; GE Healthcare, Oslo, Norway) and microdroplets (perfluorated oil) currently under development for cancer treatment. The microbubbles and microdroplets have opposite surface charges to form microbubble/microdroplet clusters, which are administered to patients together with a drug. When the clusters and drug reach the target tumour, two ultrasound (US) exposure regimes are used: First, high-frequency (>2.0 MHz) US evaporates the oil and forms ACT bubbles that lodge at the microvascular level. Second, low-frequency (0.5 MHz) US induces stable mechanical oscillations of the ACT bubbles, causing localized micro-streaming, radiation and shear forces that increase the uptake of the drugs to the target tumour. This report describes the design and testing of a dual-frequency transducer and a laboratory setup for pre-clinical in vivo studies of ACT on murine tumour models. The dual-frequency transducer utilizes the 5th harmonic (2.7 MHz) and fundamental (0.5 MHz) of a single piezoceramic disk for the high-frequency and low-frequency regimes, respectively. Two different aperture radii are used to align the high-frequency and low-frequency beam maxima, and the high-frequency -3 dB beam width diameter is 6 mm, corresponding to the largest tumour sizes we expect to treat. The low-frequency -3 dB beam width extends 6 mm. Although unconventional, the 5th harmonic exhibit a 44% efficiency and can therefore be used for transmission of acoustic energy. Moreover, both in vitro and in vivo measurements demonstrate that the 5th harmonic can be used to evaporate the microbubble/microdroplet clusters. For the in vivo measurements, we used the kidneys of non-tumour-bearing mice as tumour surrogates. Based on this, the transducer is deemed suited for pre-clinical in vivo studies of ACT and replaces a cumbersome test setup consisting of two transducers.