Therapeutic ultrasound: Its application in drug delivery

Abstract

Ultrasound is best known for its imaging capability in diagnostic medicine. However, there have been considerable efforts recently to develop therapeutic uses for it. The purpose of this review is to summarize some of the recent advances made in the area of therapeutic ultrasound as they relate to drug delivery. In particular, this review will focus on the applications of ultrasound to enhance the delivery and effect of three distinctive therapeutic drug classes: chemotherapeutic, thrombolytic, and gene-based drugs. In addition, ultrasound contrast agents have been recently developed for diagnostic ultrasound. New experimental evidence suggests that these contrast agents can be used as exogenous cavitation nuclei for enhancement of drug and gene delivery. Thus, brief review of this new class of agents and their roles in drug delivery will also be provided. By comparison to diagnostic ultrasound, progress in therapeutic use of ultrasound has been somewhat limited. The recent successes in ultrasound-related drug delivery research positions ultrasound as therapeutic tool for drug delivery in the future.

Therapeutic ultrasound-mediated DNA to cell and nucleus: bioeffects revealed by confocal and atomic force microscopy

“…11,12,20 This is believed to be due to the physical or thermal effects induced by US application. 8,9 In our studies, no significant increase in temperature was detected (o1.51C) even when using 30 min of TUS. Thus, indicating that thermal effects are not the main mechanism affecting membrane permeability and other forces, such as the mechanical ones, may play a more significant role in alteration of cell membrane.…”

“…Thus, indicating that thermal effects are not the main mechanism affecting membrane permeability and other forces, such as the mechanical ones, may play a more significant role in alteration of cell membrane. 8,9 However, this study is performed in vitro and when going to in vivo studies the thermal effect should be monitored and considered due to different absorption of the US energy by the different tissues.…”

“…This mechanical pressure may in turn reduce the unstirred layer in the local environment of the cell, thus leading to increase in DNA concentration near the cell membrane. 6,8,14 Tachibana et al 21 observed, using SEM, minor disruption of membrane cell surface due to the application of low frequency US (255 kHz). While Taniyama et al, 11 which also used SEM to study the surface of cells post-TUS application, observed almost no changes when using TUS alone.…”

“…6,9 However, TUS is known to be subcavitational due to the high frequencies and low intensities used, 4,10 thus making it hard to give an explanation for its bioeffects. Other studies also suggested that TUS might enhance gene transfection by accelerating DNA escape from endosomes, alteration of intracellular trafficking, upregulation of genes, protein translation, 5,8 or altering cell membrane permeability, thus creating pores. 11,12 Understanding the mechanism by which TUS delivers genes to cells, its bioeffects on cell membrane, the kinetics of gene entrance to the nucleus and its time of expression are crucial in order to improve transfection efficiency and allow better control of this modality.…”

“…2,3,5 Using TUS rather than low-frequency US has several advantages: It is approved for clinical application, has good penetration through soft tissues, does not damage cell and tissue and does not affect DNA integrity. 5,8 The mechanisms by which TUS mediates gene delivery into cells remains poorly understood. Cavitation is believed to play a role in almost all US modalities used for gene delivery.…”