Echocardiographic Destruction of Albumin Microbubbles Directs Gene Delivery to the Myocardium

Abstract

Background —The noninvasive, tissue-specific delivery of therapeutic agents to the heart would be a valuable clinical tool. This study addressed the hypothesis that albumin-coated microbubbles could be used to effectively deliver an adenoviral transgene to rat myocardium by ultrasound-mediated microbubble destruction. Methods and Results —Recombinant adenovirus containing β-galactosidase and driven by a constitutive promoter was attached to the surface of albumin-coated, perfluoropropane-filled microbubbles. These bubbles were infused into the jugular vein of rats with or without simultaneous echocardiography. Additional controls included ultrasound of microbubbles that did not contain virus, virus alone, and virus plus ultrasound. One group underwent ultrasound-mediated destruction of microbubbles followed by adenovirus infusion. Rats were killed after 4 days and examined for β-galactosidase expression. The hearts of all rats that underwent ultrasound-mediated destruction of microbubbles containing virus showed nuclear staining with 5-bromo-4-chloro-3-indolyl-β- d -galactopyranoside substrate, indicating expression of the transgene. None of the control animals showed myocardial expression of the β-galactosidase transgene. By quantitative analysis, β-galactosidase activity was 10-fold higher in the treated group than in controls ( P <0.0001). Conclusions —Ultrasound-mediated destruction of albumin-coated microbubbles is a promising method for the delivery of bioactive agents to the heart.