Ultrasound-induced cavitation and passive acoustic mapping: SonoTran platform performance and short-term safety in a large-animal model.

Ultrasound-induced cavitation is currently under investigation for several potential applications in cancer treatment. Among these, the use of low-intensity ultrasound, coupled with the systemic administration of various cavitation nuclei, has been found to enhance the delivery of co-administered therapeutics into solid tumors. Effective pharmacological treatment of solid tumors is often hampered, among various factors, by the limited diffusion of drugs from the bloodstream into the neoplastic mass and through it, and SonoTran holds the potential to tackle this clinical limitation by increasing the amount of drug and its distribution within the ultrasound-targeted tumor tissue.

Improved therapeutic antibody delivery to xenograft tumors using cavitation nucleated by gas-entrapping nanoparticles.

Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Tumors with strong EGF receptor expression were grown bilaterally. Cetuximab was coadministered intravenously with cavitation nuclei, consisting of either the ultrasound contrast agent Sonovue or gas-stabilizing nanoscale SonoTran Particles.

Dual-Array Passive Acoustic Mapping for Cavitation Imaging With Enhanced 2-D Resolution.

Passive acoustic mapping (PAM) techniques have been developed for the purposes of detecting, localizing, and quantifying cavitation activity during therapeutic ultrasound procedures. Implementation with conventional diagnostic ultrasound arrays has allowed planar mapping of bubble acoustic emissions to be overlaid with B-mode anatomical images, with a variety of beamforming approaches providing enhanced resolution at the cost of extended computation times. However, no passive signal processing techniques implemented to date have overcome the fundamental physical limitation of the conventional diagnostic array aperture that results in point spread functions with axial/lateral beamwidth ratios of nearly an order of magnitude.

Passive Acoustic Mapping Using Data-Adaptive Beamforming Based on Higher Order Statistics.

Sources of nonlinear acoustic emissions, particularly those associated with cavitation activity, play a key role in the safety and efficacy of current and emerging therapeutic ultrasound applications, such as oncological drug delivery, blood-brain barrier opening, and histotripsy. Passive acoustic mapping (PAM) is the first technique to enable real-time and non-invasive imaging of cavitation activity during therapeutic ultrasound exposure, through the recording and passive beamforming of broadband acoustic emissions using an array of ultrasound detectors. Initial limitations in PAM spatial resolution led to the adoption of optimal data-adaptive beamforming algorithms, such as the robust capon beamformer (RCB), that provide improved interference suppression and calibration error mitigation compared to non-adaptive beamformers.

A dual-mode hemispherical sparse array for 3D passive acoustic mapping and skull localization within a clinical MRI guided focused ultrasound device.

Previous work has demonstrated that passive acoustic imaging may be used alongside MRI for monitoring of focused ultrasound therapy. However, past implementations have generally made use of either linear arrays originally designed for diagnostic imaging or custom narrowband arrays specific to in-house therapeutic transducer designs, neither of which is fully compatible with clinical MR-guided focused ultrasound (MRgFUS) devices. Here we have designed an array which is suitable for use within an FDA-approved MR-guided transcranial focused ultrasound device, within the bore of a 3 Tesla clinical MRI scanner.

Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines.

The treatment of cancer using nanomedicines is limited by the poor penetration of these potentially powerful agents into and throughout solid tumors. Externally controlled mechanical stimuli, such as the generation of cavitation-induced microstreaming using ultrasound (US), can provide a means of improving nanomedicine delivery. Notably, it has been demonstrated that by focusing, monitoring and controlling the US exposure, delivery can be achieved without damage to surrounding tissue or vasculature.

Enhancement and Passive Acoustic Mapping of Cavitation from Fluorescently Tagged Magnetic Resonance-Visible Magnetic Microbubbles In Vivo.

Previous work has indicated the potential of magnetically functionalized microbubbles to localize and enhance cavitation activity under focused ultrasound exposure in vitro. The aim of this study was to investigate magnetic targeting of microbubbles for promotion of cavitation in vivo. Fluorescently labelled magnetic microbubbles were administered intravenously in a murine xenograft model.

Sum-of-harmonics method for improved narrowband and broadband signal quantification during passive monitoring of ultrasound therapies.

Passive Acoustic Mapping (PAM) enables real-time monitoring of ultrasound therapies by beamforming acoustic emissions emanating from the ultrasound focus. Reconstruction of the narrowband or broadband acoustic emissions component enables mapping of different physical phenomena, with narrowband emissions arising from non-linear propagation and scattering, non-inertial cavitation or tissue boiling, and broadband (generally, of significantly lower amplitude) indicating inertial cavitation. Currently, accurate classification of the received signals based on pre-defined frequency-domain comb filters cannot be guaranteed because varying levels of leakage occur as a function of signal amplitude and the choice of windowing function.

Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus.

Oncolytic viruses (OV) could become the most powerful and selective cancer therapies. However, the limited transport of OV into and throughout tumors following intravenous injection means their clinical administration is often restricted to direct intratumoral dosing. Application of physical stimuli, such as focused ultrasound, offers a means of achieving enhanced mass transport.

Ultrasound-Propelled Nanocups for Drug Delivery.

Ultrasound-induced bubble activity (cavitation) has been recently shown to actively transport and improve the distribution of therapeutic agents in tumors. However, existing cavitation-promoting agents are micron-sized and cannot sustain cavitation activity over prolonged time periods because they are rapidly destroyed upon ultrasound exposure. A novel ultrasound-responsive single-cavity polymeric nanoparticle (nanocup) capable of trapping and stabilizing gas against dissolution in the bloodstream is reported.

Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring.

Passive acoustic mapping (PAM) is a promising imaging method that enables real-time three-dimensional monitoring of ultrasound therapy through the reconstruction of acoustic emissions passively received on an array of ultrasonic sensors. A passive beamforming method is presented that provides greatly improved spatial accuracy over the conventionally used time exposure acoustics (TEA) PAM reconstruction algorithm. Both the Capon beamformer and the robust Capon beamformer (RCB) for PAM are suggested as methods to reduce interference artifacts and improve resolution, which has been one of the experimental issues previously observed with TEA.

Passive acoustic mapping of magnetic microbubbles for cavitation enhancement and localization.

Magnetic targeting of microbubbles functionalized with superparamagnetic nanoparticles has been demonstrated previously for diagnostic (B-mode) ultrasound imaging and shown to enhance gene delivery in vitro and in vivo. In the present work, passive acoustic mapping (PAM) was used to investigate the potential of magnetic microbubbles for localizing and enhancing cavitation activity under focused ultrasound. Suspensions of magnetic microbubbles consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), air and 10 nm diameter iron oxide nanoparticles were injected into a tissue mimicking phantom at different flow velocities (from 0 to 50 mm s(-1)) with or without an applied magnetic field.

Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery.

New classes of biologically active materials, such as viruses, siRNA, antibodies and a wide range of engineered nanoparticles have emerged as potent agents for diagnosing and treating diseases, yet many of these agents fail because there is no effective route of delivery to their intended targets. Focused ultrasound and its ability to drive microbubble-seeded cavitation have been shown to facilitate drug delivery. However, cavitation is difficult to control temporally and spatially, making prediction of therapeutic outcomes deep in the body difficult.

Thin-film sparse boundary array design for passive acoustic mapping during ultrasound therapy.

A new 2-D hydrophone array for ultrasound therapy monitoring is presented, along with a novel algorithm for passive acoustic mapping using a sparse weighted aperture. The array is constructed using existing polyvinylidene fluoride (PVDF) ultrasound sensor technology, and is utilized for its broadband characteristics and its high receive sensitivity. For most 2-D arrays, high-resolution imagery is desired, which requires a large aperture at the cost of a large number of elements.

Passive cavitation mapping with temporal sparsity constraint.

The spatial resolution of cavitation maps generated from passive recordings of cavitation emissions is compromised by the bandlimited nature of the recordings. Deconvolution based on the assumption that cavitation consists of a sparse series of discrete events allows the recovery of frequency components that are not only outside the frequency band of the receivers, but may also have been attenuated by the medium before being detectable. In the current work, two sparse deconvolution techniques, matching pursuit and basis pursuit, were applied to simulated and experimental cavitation recordings before they were beamformed to provide passive maps of cavitation activity.