Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-08, Vol.108 (8), p.1022-1026
• Main Authors: BEKEREDJIAN, Raffi, SHUYUAN CHEN, FRENKEL, Peter A, GRAYBURN, Paul A, SHOHET, Ralph V
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Contrast Media - administration & dosage; Cytomegalovirus - genetics; Diseases of the cardiovascular system; Gene Expression; Genes, Reporter; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Heart - drug effects; Luciferases - analysis; Luciferases - biosynthesis; Luciferases - genetics; Medical sciences; Microspheres; Myocardium - cytology; Myocardium - metabolism; Organ Specificity - genetics; Plasmids - administration & dosage; Plasmids - genetics; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Rats; Rats, Sprague-Dawley; Reproducibility of Results; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; Time Factors; Transgenes; Ultrasonic Therapy - methods
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000084535.35435.AE

Noninvasive, tissue-specific delivery of therapeutic agents would be a valuable clinical tool. We have previously shown that ultrasound-targeted microbubble destruction can direct expression of an adenoviral reporter to the heart. The present study shows that this method can be applied to selectively deliver plasmid vectors to the heart. We used albumin and lipid microbubbles containing plasmids with a luciferase transgene to target the heart in rats. After 4 days, organs were harvested and analyzed for reporter gene expression. In a second set of experiments, the hearts of rats treated with plasmids were harvested at various time points during a 4-week period. Both luciferase activity and mRNA concentrations were measured. Luciferase transfection with plasmids showed highly specific gene expression in the heart, with hardly any activity in control organs. Time course evaluation showed high transgene expression in the first 4 days, with a rapid decline thereafter. Repeated treatment produced a second peak of transgene expression with similar decay. Ultrasound-mediated destruction of microbubbles directs plasmid transgene expression to the heart with much greater specificity than viral vectors and can be regulated by repeated treatments. This noninvasive technique is a promising method for cardiac gene therapy.