Passive acoustic mapping of extravasation following ultrasound-enhanced drug delivery

Abstract

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.

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

“…However, the value of this expansion would depend on the intended application. For in vitro [21] and ongoing preclinical in vivo work, only a small portion of the overlapping FoVs of the array pair (which is necessarily smaller than a single array FoV) has been needed. For clinical therapeutic FUS applications where it is of interest to limit potential off-target damage, evidence of cavitation would be sought throughout the full propagation path of the FUS beam, including pre-and post-focally.…”

“…The array pair was configured with a 90° separation angle in the imaging (y-z) plane by mounting each array to the back of a FUS transducer, each of which was held in a Delrin thermoplastic 'L' bracket (not shown) that set the device orientations and radii to a common focal point [21]. This orthogonal arrangement was expected to provide superior image quality by applying the fine inherent lateral resolution of each array to both axes of the imaging plane.…”

“…In the frequency range where conventional arrays are both available and broadly applicable to clinical work (<10 MHz for depths of several cm), the ability to localize and separate cavitation events may not be adequate either for laboratory or clinical application. In particular, submillimeter feature localization would be desirable for detailed studies of intra-and extra-vascular bubble behavior and particle transport [20,21], particularly in murine pre-clinical models where the tumor diameter is commonly 4-10 mm [22].…”

Oxford’s clinical experience in the development of high intensity focused ultrasound therapy

“…The aim of the TARDOX trial [29][30][31][32] was to assess the safety and feasibility of delivering doxorubicin to solid tumours via thermosensitive liposomes. This was a phase I trial conducted at Churchill Hospital.…”

Spatiotemporal Assessment of the Cellular Safety of Cavitation-Based Therapies by Passive Acoustic Mapping

“…To avoid these problems, arrays of transducers can be used in combination with beamforming algorithms such as passive acoustic mapping (PAM), which uses the relative time of arrival between different elements of the array to allow for the localisation and spatial segregation between the sources of acoustic emissions in both the time (Gy€ ongy et al 2008;Salgaonkar et al 2009;Coussios 2010a, 2010b;O'Reilly et al 2014) and frequency (Haworth et al 2017;Abadi et al 2018) domains. More recently, the development of optimized passive beamforming algorithms (Coviello et al 2015;Lyka et al 2016) has led to significant improvements in the spatial resolution of PAM in localizing the position and extent of cavitation both in vitro and in vivo (Choi et al 2014;Crake et al 2016;Paverd et al 2019).…”