Ultrasound mediated microbubble cavitation for treatment and monitoring of cancer

Abstract

Microbubbles, typically used as a diagnostic ultrasound contrast agent to improve blood flow visualization, also holds great promise as a therapeutic agent for treatment of solid tumors. When insonified by an acoustic pulse, microbubbles undergo volumetric oscillations, providing both an acoustic signal for image contrast enhancement and localized microscale forces during cavitation. These microscale forces can induce several biological effects that overcome the barriers to treating solid tumors, including increased cell membrane permeability, enhanced drug delivery, and tumor-specific vascular changes. In this thesis, we present several investigations of how ultrasound and microbubbles can be applied as both a therapeutic and monitoring strategy for treating cancer. We begin with an introduction on microbubble cavitation and its capacity to monitor and modulate the tumor microenvironment (Chapter 1). First, we implement acoustic conditions suitable for generating mechanical forces with cavitation therapy on a clinical scanner and determine which acoustic conditions maximize cavitation activity in vitro (Chapter 2). We then investigate the mechanical effects of cavitation therapy in vivo, using real-time monitoring to elucidate mechanisms of changes to the tumor microenvironment and enhancement of drug delivery to solid tumors (Chapter 3). Next, we evaluate the enhanced heat deposition during cavitation therapy in an ex vivo machine perfused liver model, evaluating acoustic pressure and microbubble delivery methods to increase temperature and heated area (Chapter 4). We then implement subharmonic imaging on a clinical scanner for noninvasive estimation of interstitial fluid pressure in solid tumors and evaluate the mode’s ambient pressure sensitivity in physiological ranges for a range of acoustic pressures and microbubble formulations (Chapters 5 and 6). We conclude with a summary of the accomplishments and future directions of this work (Chapter 7).