Contrast Ultrasound Targeted Drug and Gene Delivery: An Update on a New Therapeutic Modality

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Abstract
The effective delivery of intravascular drugs and genes to regions of pathology is dependent on a number of factors that are often difficult to control. Foremost is the site-specific delivery of the payload to the region of pathology and the subsequent transport of the payload across the endothelial barrier. Ultrasound contrast agent microbubbles, which are typically used for image enhancement, are capable of amplifying both the targeting and transport of drugs and genes to tissue. Microbubble targeting can be achieved by the intrinsic binding properties of the microbubble shells or through the attachment of site-specific ligands. Once microbubbles have been targeted to the region of interest, microvessel walls can be permeabilized by destroying the microbubbles with low-frequency, high-power ultrasound. A second level of targeting specificity can be achieved by carefully controlling the ultrasound field and limiting microbubble destruction to the region of interest. When microbubbles are destroyed, drugs or genes that are housed within them or bound to their shells can be released to the blood stream and then delivered to tissue by convective forces through the permeabilized microvessels. An alternative strategy is to increase payload volume by coinjecting drug or gene-bearing vehicles, such as liposomes, with the microbubbles. In this manifestation, microbubbles are used for creating sites of microvessel permeabilization that facilitate drug or gene vehicle transport. Recent work in the emerging field of contrast ultrasound-based therapeutics, with particular emphasis on the delivery of drugs and genes to tissue through microvascular networks is reviewed.