The role of ultrasound-driven microbubble dynamics in drug delivery : from microbubble fundamentals to clinical translation

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

Ultrasound assisted siRNA delivery using PEG-siPlex loaded microbubbles

Short interfering RNA (siRNA) attracts much attention for the treatment of various diseases. However, its delivery, especially via systemic routes, remains a challenge. Indeed, naked siRNAs are rapidly degraded, while complexed siRNAs massively aggregate in the blood or are captured by macrophages. Although this can be circumvented by PEGylation, we found that PEGylation had a strong negative effect on the gene silencing efficiency of siRNA-liposome complexes (siPlexes). Recently, ultrasound combined with microbubbles has been used to deliver naked siRNA but the gene silencing efficiency is rather low and very high amounts of siRNA are required. To overcome the negative effects of PEGylation and to enhance the efficiency of ultrasound assisted siRNA delivery, we coupled PEGylated siPlexes (PEG-siPlexes) to microbubbles. Ultrasound radiation of these microbubbles resulted in massive release of unaltered PEG-siPlexes. Interestingly, PEG-siPlexes loaded on microbubbles were able to enter cells after exposure to ultrasound, in contrast to free PEG-siPlexes, which were not able to enter cells rapidly. Furthermore, these PEG-siPlex loaded microbubbles induced, in the presence of ultrasound, much higher gene silencing than free PEG-siPlexes. Additionally, the PEG-siPlex loaded microbubbles only silenced the expression of genes in the presence of ultrasound, which allows space and time controlled gene silencing

Plasmonic Bubbles in n-Alkanes

In this paper we study the formation of microbubbles upon the irradiation of an array of plasmonic Au nanoparticles with a laser in n-alkanes ($C_{n}H_{2n+2}$, with n = 5-10). Two different phases in the evolution of the bubbles can be distinguished. In the first phase, which occurs after a delay time {\tau}d of about 100 {\mu}s, an explosive microbubble, reaching a diameter in the range from 10 {\mu}m to 100 {\mu}m, is formed. The exact size of this explosive microbubble barely depends on the carbon chain length of the alkane, but only on the laser power $P_l$. With increasing laser power, the delay time prior to bubble nucleation as well as the size of the microbubble both decrease. In the second phase, which sets in right after the collapse of the explosive microbubble, a new bubble forms and starts growing due to the vaporization of the surrounding liquid, which is highly gas rich. The final bubble size in this second phase strongly depends on the alkane chain length, namely it increases with decreasing number of carbon atoms. Our results have important implications for using plasmonic heating to control chemical reactions in organic solvents