Abstract
Pancreatic ductal adenocarcinomas respond poorly to chemotherapy, in part due to the dense tumor stroma that hinders drug delivery. Ultrasound (US) in combination with microbubbles has previously shown promise as a means to improve drug delivery, and the therapeutic efficacy of ultrasound-mediated drug delivery is currently being evaluated in multiple clinical trials. However, most of these utilize echogenic contrast agents engineered for imaging, which might not be optimal compared to specialized formulations tailored for drug delivery. In this study, we evaluated the in vivo efficacy of phase-shifting microbubble-microdroplet clusters that, upon insonation, form bubbles in the size range of 20–30 μm. We developed a patient-derived xenograft model of pancreatic cancer implanted in mice that largely retained the stromal content of the originating tumor and compared tumor growth in mice given chemotherapeutics (nab-paclitaxel plus gemcitabine or liposomal irinotecan) with mice given the same chemotherapeutics in addition to ultrasound and acoustic cluster therapy. We found that acoustic cluster therapy significantly improved the effect of both chemotherapeutic regimens and resulted in 7.2 times higher odds of complete remission of the tumor compared to the chemotherapeutics alone.