Cavitation enhanced drug delivery in-vivo using combined B-mode guidance and real-time passive acoustic mapping: Challenges and results

Abstract

Inertial cavitation nucleated by nano-scale sonosensitive particles (SSPs) at modest peak negative pressures (~1 MPa at 500 kHz) and monitored by passive acoustic mapping (PAM) has been recently shown to improve the dose and distribution of anti-cancer agents during ultrasound (US) enhanced delivery (Myers 2016, Kwan 2015). As applications of therapy monitoring using PAM have advanced rapidly including its use in clinical trials, means of validating the performance of PAM in-vivo remains a major focus of efforts. For drug delivery, PAM should not only quickly and reliably detect and localize desired and undesired cavitation, but it should provide some predictor of successful delivery. In-vivo experiments using PAM in subcutaneous tumor implanted murine models across a range of cancer cell lines (HEPG2, SKOV, EMT6, CT-26) demonstrate the detection of inertial cavitation by SSPs in the target regions when sonicated by US, but no cavitation with US alone. Additionally when SSPs are co-administered with an oncolytic virus (vaccinia), a small molecule chemotherapeutic (doxorubicin), or an immunotherapeutic (anti-PD-L1 antibody), PAM is able to effectively predict successful delivery in the presence of cavitation in the target regions and unsuccessful delivery in the absence of cavitation in target regions. Enhancements to PAM to deal with artifacts, spurious reflections, and to increase resolution were also able to improve the monitoring capability. Future work focuses on clinical translation and improved validation methods.