Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery.

Abstract

Ultrasound-mediated delivery facilitated by microbubbles provides a novel means for intracellular drug and gene delivery and particularly a noninvasive strategy uniquely suitable for clinical applications. Spatiotemporally controllable application of ultrasound energy combined with microbubbles make it possible for site-specific delivery of therapeutic agents to the region-of-interest with minimal undesirable systemic side effects. By inducing rapid expansion/contraction and/or collapse of microbubbles, ultrasound application can temporarily increase the cell membrane permeability (sonoporation) to create a physical route for impermeable agents to enter the cells. Sonoporation is transient and dynamic, involving complex processes of bubble physics, bubble–cell interactions, and subsequent cellular effects that all affect the ultimate delivery outcome. This review summarizes the studies on the important aspects of the mechanisms of ultrasound-mediated delivery, provides illustrative examples of applications, and discusses the challenges and limitations of the technique. Microbubbles have been used for several decades as a contrast agent for ultrasound imaging [1]. The small size of microbubbles allows them access to well-perfused organs when injected into the vasculature, and their gas core efficiently reflects and scatters the incident ultrasound field, thereby increasing image contrast between the vasculature and the surrounding tissue. Recent developments in microbubble technology have enabled molecular imaging via targeting of the microbubbles to molecular markers of disease expressed on the surface of cells [2]. In addition to imaging, innovation in microbubbles has opened new opportunities for targeted drug and gene delivery. Ultrasound excitation of microbubbles has been exploited to increase vascular and cell membrane permeability and facilitate the passage of therapeutic agents across the vascular barrier and cell membrane into the cytoplasm for drug and gene transfection [3–7]. The ultrasound delivery technique, with the advantage of noninvasive, spatiotemporaly controllable ultrasound application combined with functionalized micro-bubbles, holds great promise to provide new therapeutic strategies. However, even with recent progress in the field, challenges remain, including relatively low delivery efficiency and large variation of delivery outcome. Better understanding of the underlying mechanisms is thus of great importance to optimize this technique and promote its translation towards clinical application. Although the mechanisms of ultrasound- and microbubble-facilitated intracellular delivery have not yet been fully understood, a direct physical route of transport often termed sonoporation is most likely involved [8–10]. The dynamic response of the microbubbles driven by ultrasound as well as the interaction between the microbubbles and the cell membrane are key factors in determining delivery efficiency. Other factors such as the cellular response, the kinetics and metabolism of therapeutic agents in the cytoplasm, also play important roles in the ultimate outcome of ultrasound-mediated delivery. In this review, we first summarize progress in these aspects and then discuss limitations and challenges that the technique currently faces.