Ultrasound-mediated drug delivery for cardiovascular disease

Abstract

Introduction: Ultrasound (US) has been developed as both a valuable diagnostic tool and a potent promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. These effects can be mediated by mechanical oscillations of circulating microbubbles, or US contrast agents, which may also encapsulate and shield a therapeutic agent in the bloodstream. Oscillating microbubbles can create stresses directly on nearby tissue or induce fluid effects that effect drug penetration into vascular tissue, lyse thrombi or direct drugs to optimal locations for delivery.

Areas covered: The present review summarizes investigations that have provided evidence for US-mediated drug delivery as a potent method to deliver therapeutics to diseased tissue for cardiovascular treatment. In particular, the focus will be on investigations of specific aspects relating to US-mediated drug delivery, such as delivery vehicles, drug transport routes, biochemical mechanisms and molecular targeting strategies.

Expert opinion: These investigations have spurred continued research into alternative therapeutic applications, such as bioactive gas delivery and new US technologies. Successful implementation of US-mediated drug delivery has the potential to change the way many drugs are administered systemically, resulting in more effective and economical therapeutics, and less-invasive treatments.

Figure 1. An overview of three penetration routes stimulated for ultrasound-mediated drug delivery

Sonoporation refers to the localized, mechanical disruption of a plasma membrane, which allows drugs and ions to diffuse passively. Transcellular pathways, such as endocytosis, involve active transport of drug via cytosolic vesicles. The paracellular route occurs when endothelial cells spread apart, either due to desquamation or by tight junction breakdown from bubble-induced shear stress.

Figure 2. An overview of some proposed mechanisms for transcellular and paracellular ultrasound-mediated drug delivery

Transcellular: as a result of bubble-induced shear stress along the cell membrane, extracellular drugs can undergo caveolin-1-mediated endocytosis. Additionally, sonoporation can create ‘holes’ in the cell membrane facilitating influx of ions or drugs. Paracellular: shear stress from cavitation-induced microstreaming can cause caveolin-1 to detach from endothelial nitric oxide synthase (eNOS). Here, it converts arginine to nitric oxide, stimulating vasodilation and possible paracellular permeability. Alternatively, this shear stress deforms the actin cytoskeleton, which can cause conformational changes and breakdown of tight junction proteins (ZO-1, occludin).

Figure 3. Propidium iodide (PI; left column) and intracellular [Ca²⁺]_i flux (right column) during microbubble oscillation near a cell membrane

Cell outlines, indicated by white lines, demarcate PI and Ca²⁺ delivery, when a bubble (circle) oscillates near its cell membrane. The initial state of the cell is seen in the first row, followed by subsequent images during ultrasound exposure. Reprinted from Fan et al. [133], with permission from Elsevier (2012).

Figure 4. Images of calcein fluorescence indicating penetration of liposomes targeting to smooth muscle actin, in the absence (left) and presence (right) of ultrasound

Reprinted from Laing et al. [112], with permission from Informa Healthcare (2012).

Figure 5. Cavitational mechanisms in sonothrombolysis

As a result of local fluid dynamics around a cavitating microbubbles, the fibrinolytic enzymes (recombinant tissue-plasminogen activator (rt-PA) and plasminogen) penetrate deeper into the fibrin matrix. Additionally, fluid microstreaming removes fibrin degradation products from the surface of the clot, expediting the fibrinolytic process.