Ultrasonic drug delivery--a general review

Abstract

Ultrasound has an ever-increasing role in the delivery of therapeutic agents, including genetic material, protein and chemotherapeutic agents. Cavitating gas bodies, such as microbubbles, are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilise cell membranes and disrupt the vesicles that carry drugs. Thus, the presence of microbubbles enormously enhances ultrasonic delivery of genetic material, proteins and smaller chemical agents. Numerous reports show that the most efficient delivery of genetic material occurs in the presence of cavitating microbubbles. Attaching the DNA directly to the microbubbles, or to gas-containing liposomes, enhances gene uptake even further. Ultrasonic-enhanced gene delivery has been studied in various tissues, including cardiac, vascular, skeletal muscle, tumour and even fetal tissue. Ultrasonic-assisted delivery of proteins has found most application in transdermal transport of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; and makes cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has on cells and drug-carrying vesicles.

Figure 1

Optical images of a 2.5 μm-radius microbubble exposed to 5 cycles of 2.5 MHz ultrasound at 1.6 MPa pressure amplitude. The left panel shows the bubble before exposure. The central panel shows a streak photograph (an optical M-mode image of a line through the center of the bubble as a function of time) with the measured pressure superimposed at the top of the panel. The right panel shows bubble the fragments produced by the collapse of the cavitating bubble. Taken from [12]. Copyright IEEE.

Figure 2

Illustration of an asymmetric collapse of a bubble near a surface, producing a jet of liquid toward the surface.

Figure 3

Schematic representation of various modes by which drug delivery can be enhanced by ultrasound. A: therapeutic agent (triangles); B: gas bubble undergoing stable cavitation; C: microstreaming around cavitating bubble; D. collapse cavitation emitting a shock wave; E: asymmetrical bubble collapse producing a liquid jet that pierces the endothelial lining; F: completely pierced and ruptured cell; G: non-ruptured cells with increased membrane permeability due to insonation; H: cell with damaged membrane from microstreaming or shock wave; I: extravascular tissue; J: thin-walled microbubble decorated with agent on surface; K. thick-walled microbubble with agent in lipophilic phase; L: micelle with agent in lipophilic phase; M: liposome with agent in aqueous interior; N: vesicle decorated with targeting moieties attached to a specific target.