Echocardiographic destruction of albumin microbubbles directs gene delivery to the myocardium.

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 beta-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 beta-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-beta-D-galactopyranoside substrate, indicating expression of the transgene. None of the control animals showed myocardial expression of the beta-galactosidase transgene. By quantitative analysis, beta-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.

[1]  M. Post,et al.  Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. , 1999, Circulation.

[2]  P. Grayburn,et al.  Clinical applications of transpulmonary contrast echocardiography. , 1999, American heart journal.

[3]  T C Skalak,et al.  Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound. , 1998, Circulation.

[4]  T C Skalak,et al.  Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and Its Local Effects on Tissue. , 1998, Circulation.

[5]  A. Feldman,et al.  Gene therapy for therapeutic myocardial angiogenesis: A promising synthesis of two emerging technologies , 1998, Nature Medicine.

[6]  C. Nielsen,et al.  Systematics: Sequences lead to tree of worms , 1998, Nature.

[7]  E. Unger,et al.  Ultrasound enhances gene expression of liposomal transfection. , 1997, Investigative radiology.

[8]  M. Kay,et al.  Gene therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  I. Verma,et al.  Gene therapy - promises, problems and prospects , 1997, Nature.

[10]  S. Kaul,et al.  Interactions between microbubbles and ultrasound: in vitro and in vivo observations. , 1997, Journal of the American College of Cardiology.

[11]  T. Porter,et al.  Detection of myocardial perfusion in multiple echocardiographic windows with one intravenous injection of microbubbles using transient response second harmonic imaging. , 1997, Journal of the American College of Cardiology.

[12]  C. Newgard,et al.  Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Iversen,et al.  Interaction of diagnostic ultrasound with synthetic oligonucleotide‐labeled perfluorocarbon‐exposed sonicated dextrose albumin microbubbles. , 1996, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[14]  M Vapalahti,et al.  [Human gene therapy]. , 1996, Duodecim; laaketieteellinen aikakauskirja.

[15]  S. Rosenberg,et al.  T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years , 1995, Science.

[16]  E. Nabel,et al.  Gene therapy for cardiovascular disease. , 1995, Circulation.

[17]  B. A. French,et al.  Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. , 1994, Circulation.

[18]  James M. Wilson,et al.  Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. , 1994, Gene therapy.

[19]  L. Leinwand,et al.  Quantitative determination of adenovirus-mediated gene delivery to rat cardiac myocytes in vitro and in vivo. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Crystal,et al.  Efficient gene transfer into myocardium by direct injection of adenovirus vectors. , 1993, Circulation research.

[21]  S. Bolling,et al.  Expression of recombinant genes in myocardium in vivo after direct injection of DNA. , 1990, Circulation.

[22]  M. Yamada.  [Adenovirus vectors]. , 1986, Uirusu.

[23]  D. Glover.  DNA cloning : a practical approach , 1985 .