Aims: Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Methods: 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. One of the two tumors was exposed to focused ultrasound. Passive acoustic mapping localized and monitored cavitation activity. Both tumors were then excised and cetuximab concentration was quantified. Results: Cavitation increased tumoral cetuximab concentration. When nucleated by Sonovue, a 2.1-fold increase (95% CI 1.3- to 3.4-fold) was measured, whereas SonoTran Particles gave a 3.6-fold increase (95% CI 2.3- to 5.8-fold). Conclusions: Ultrasound-mediated cavitation, especially when nucleated by nanoscale gas-entrapping particles, can noninvasively increase site-specific delivery of therapeutic antibodies to solid tumors.

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. However, such approaches are restricted by the assumption that the recorded signals have a Gaussian distribution. To overcome this limitation and further improve the source resolvability of PAM, we propose a new beamforming approach termed robust beamforming by linear programming (RLPB). Along with the variance, this optimization-based method uses higher-order-statistics of the recorded signals, making no prior assumption on the statistical distribution of the acoustic signals. The RLPB is found via numerical simulations to improve resolvability over time exposure acoustics and RCB. In vitro experimentation yielded improved resolvability with respect to the source-to-array distance on the order of 22% axially and 13% transversely relative to RCB, whilst successfully accounting for array calibration errors. The improved resolution and decreased dependence on accurate calibration of RLPB is expected to facilitate the clinical translation of PAM for diagnostic, including super-resolution, and therapeutic ultrasound applications.

The amount and distribution of chemotherapeutic agents delivered to tumours can vary significantly due to tumour heterogeneity, even under Focussed Ultrasound (FUS) assisted drug delivery regimes. The ability to non-invasively localise cavitation nuclei of a similar size to therapeutic drugs, both within the vasculature and tumour tissue, may provide a useful marker of ultrasoundenhanced drug delivery and extravasation. Solid polymer based nanoscale cavitation nuclei, under FUS excitation, have previously been shown to extravasate into tissue-mimicking phantoms, and to increase drug delivery in murine tumour models in vivo. Here we show in a tissue-mimicking material that these nuclei, once extravasated under FUS excitation, are still acoustically active and can be non-invasively localised using Passive Acoustic Mapping (PAM). By using a high resolution dual linear array setup in conjunction with adaptive beamformers, we demonstrate that the average 'Maximum Distance' of a PAM pixel to an extravasated particle across experiments is 0.4 ± 0.2 mm. Although the primary objective of the paper is to show that extravascular cavitation can be used as evidence of successful drug extravasation in a tissue-mimicking phantom, we also recognise the physical and computational limitations of using a high resolution dual array setup with adaptive beamformers. Thus as a secondary objective, we evaluate tradeoffs between adaptive and non-adaptive beamformers, as well as between dual and single array geometries. When compared to a conventional beamformer, adaptive beamformers reduce the maximum distance of PAM pixels to extravasated particles from an average of 2.4 ± 0.7 mm to 1.8 ± 0.6 mm in the single array case. The distance is further reduced to 0.4 ± 0.2 mm using the dual array configuration, thereby demonstrating that increasing the solid angle spanned by the PAM array aperture significantly improves drug delivery localisation. Future work will test the applicability of PAM-based monitoring of ultrasoundenhanced drug delivery in vivo.

There is a growing interest in quantifying shear-wave dispersion (SWD) with ultrasound shear-wave elastography (SWE). Recent studies suggest that SWD complements shear-wave speed (SWS) in diffuse liver disease diagnosis. To accurately interpret these metrics in clinical practice, we analyzed the impact of operatordependent acquisition parameters on SWD and SWS measurements. Considered parameters were the acquisition depth, lateral position and size of the region of interest (ROI), as well as the size of the SWE acquisition box. Measurements were performed using the Canon Aplio i800 system (Canon Medical Systems, Otawara, Tochigi, Japan) and four homogeneous elasticity phantoms with certified stiffness values ranging from 3.7 to 44 kPa. In general, SWD exhibited two to three times greater variability than SWS. The acquisition depth was the main variance-contributing factor for both SWS and SWD, which decayed significantly with depth. The lateral ROI position contributed as much as the acquisition depth to the total variance in SWD. Locations close to the initial shear-wave excitation pulse were more robust to biases because of inaccurate probeÀphantom coupling. The size of the ROI and acquisition box did not introduce significant variations. These results suggest that future guidelines on multiparametric elastography should account for the depth-and lateral-dependent variability of measurements.