The Role of Ultrasound-Driven Microbubble Dynamics in Drug Delivery: From Microbubble Fundamentals to Clinical Translation

Silke Roovers,Michel Versluis,Joke Deprez,Tim Segers,Stefaan C De Smedt,Ine Lentacker,Guillaume Lajoinie

doi:10.1021/acs.langmuir.8b03779

Abstract

In the last couple of decades, ultrasound-driven microbubbles have proven excellent candidates for local drug delivery applications. Besides being useful drug carriers, microbubbles have demonstrated the ability to enhance cell and tissue permeability and, as a consequence, drug uptake herein. Notwithstanding the large amount of evidence for their therapeutic efficacy, open issues remain. Because of the vast number of ultrasound- and microbubble-related parameters that can be altered and the variability in different models, the translation from basic research to (pre)clinical studies has been hindered. This review aims at connecting the knowledge gained from fundamental microbubble studies to the therapeutic efficacy seen in in vitro and in vivo studies, with an emphasis on a better understanding of the response of a microbubble upon exposure to ultrasound and its interaction with cells and tissues. More specifically, we address the acoustic settings and microbubble-related parameters (i.e., bubble size and physicochemistry of the bubble shell) that play a key role in microbubble-cell interactions and in the associated therapeutic outcome. Additionally, new techniques that may provide additional control over the treatment, such as monodisperse microbubble formulations, tunable ultrasound scanners, and cavitation detection techniques, are discussed. An in-depth understanding of the aspects presented in this work could eventually lead the way to more efficient and tailored microbubble-assisted ultrasound therapy in the future.

Highlights

Over the last decades, ultrasound has become an essential tool in diagnostic imaging due to its costeffective, noninvasive and safe nature[1,2]
A vast amount of work has focused on elucidating the mechanical response of a microbubble to ultrasound in terms of the acoustic parameters on the one hand, and microbubble characteristics, i.e. bubble size and physico-chemistry of the bubble shell, on the other hand. In this part we describe what determines the dynamics of a microbubble in response to an ultrasound driving pulse and summarize which aspects are relevant for drug delivery
Concluding remarks Microbubble and ultrasound-driven drug delivery has been extensively studied with promising outcome which even resulted in the first clinical trials

Summary

Introduction

Ultrasound has become an essential tool in diagnostic imaging due to its costeffective, noninvasive and safe nature[1,2]. It was found that injecting saline containing a small dose of tiny gas bubbles tremendously improved the contrast in an ultrasound image[4,5]. The first clinically approved gasfilled microbubbles for diagnostic imaging were introduced. These micron-sized (1-10 micron in diameter) gas bubbles can be intravenously administered and consist of a gaseous core surrounded by a protective shell to extend their lifetime. Bio-inspired phospholipid-coated shells are of particular interest since they provide a high flexibility while maintaining sufficient resistance to gas diffusion. They are the main bubble type encountered both in research and in the clinic, and will be the focus of this review. Apart from the commercial phospholipid-coated microbubble formulations, such as Definity® (Lantheus), Sonazoid® (GE Healthcare) and Sonovue® (Bracco), custom-designed lipid-shelled microbubbles are frequently used in in vivo and in vitro studies since they allow coupling of targeting agents[10,11,12,13], drug carriers[10,11,12,14,15] and multimodal imaging agents[16,17,18]

Objectives

Conclusion