Microbubble Contrast Agents: Targeted Ultrasound Imaging and Ultrasound-Assisted Drug-Delivery Applications

The use of microbubble contrast agents for general tissue delineation and perfusion enjoys steady interest in ultrasound imaging. Microbubbles as contrast materials require a small dosage and show excellent detection sensitivity. Targeting ligands on the surface of microbubbles permit the selective accumulation of these particles in the areas of interest, which show an up-regulated level of receptor molecules on vascular endothelium. Selective contrast imaging of inflammation, ischemia–reperfusion injury, angiogenesis, and thrombosis has been achieved in animal models. Ultrasound-assisted drug delivery and activation, performed by combining microbubble agent containing drug substances or coadministered with pharmaceutical agents (including plasmid DNA for transfection), has been achieved in multiple model systems in vitro and in vivo. Ultrasound and microbubbles-based targeted acceleration of the thrombolytic enzyme action already have reached clinical trials. Overall, microbubble targeting and ultrasound-assisted microbubble-based drug-delivery systems will offer a step toward the application of targeted personalized diagnostics and therapy.

[1]  M. Wheatley,et al.  Preparation and characterization of hollow microcapsules for use as ultrasound contrast agents , 1999 .

[2]  David Needham,et al.  The Influence of Tiered Layers of Surface-Grafted Poly(ethylene glycol) on Receptor−Ligand-Mediated Adhesion between Phospholipid Monolayer-Stabilized Microbubbles and Coated Glass Beads , 2000 .

[3]  Jonathan R. Lindner,et al.  Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to &agr;v&bgr;3 , 2003 .

[4]  K. Ohmori,et al.  Enhancement of ultrasound-accelerated thrombolysis by echo contrast agents: dependence on microbubble structure. , 1999, Ultrasound in medicine & biology.

[5]  Sanjiv Kaul,et al.  Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles. , 2003, Ultrasound in medicine & biology.

[6]  W. Wagner,et al.  Targeting and ultrasound imaging of microbubble-based contrast agents , 1999, Magnetic Resonance Materials in Physics, Biology and Medicine.

[7]  William R Wagner,et al.  Ultrasonic imaging of tumor angiogenesis using contrast microbubbles targeted via the tumor-binding peptide arginine-arginine-leucine. , 2005, Cancer research.

[8]  M. Kohno,et al.  Interaction with leukocytes: phospholipid-stabilized versus albumin-shell microbubbles. , 2004, Radiology.

[9]  Simon C Watkins,et al.  Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. , 1998, Circulation.

[10]  E. Unger,et al.  Targeted-Microbubble Binding Selectively to GPIIb IIIa Receptors of Platelet Thrombi , 2002, Investigative radiology.

[11]  Jiri Sklenar,et al.  Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to alpha(v)beta3. , 2003, Circulation.

[12]  Michael Reinhardt,et al.  Molecular targeting of lymph nodes with L-selectin ligand-specific US contrast agent: a feasibility study in mice and dogs. , 2004, Radiology.

[13]  R. Reszka,et al.  Pharmaceutical Evaluation of Gas-Filled Microparticles as Gene Delivery System , 2004, Pharmaceutical Research.

[14]  Y Wu,et al.  Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. , 1998, Investigative radiology.

[15]  M. Kohno,et al.  Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model , 2004, Circulation.

[16]  E. Gertz,et al.  Detection of Coronary Artery Stenosis With Power Doppler Imaging , 2001, Circulation.

[17]  Georg Bartsch,et al.  Gene therapy strategies in prostate cancer. , 2005, Current gene therapy.

[18]  Ultrasonic analysis of peptide- And antibody-targeted microbubble contrast agents for molecular imaging of α vβ 3-expressing cells , 2004 .

[19]  D. McPherson,et al.  Intravascular ultrasound molecular imaging of atheroma components in vivo. , 2004, Journal of the American College of Cardiology.

[20]  D. Cosgrove,et al.  Stimulierte akustische Emission mit dem Ultraschall-Kontrastmittel Levovist: Ein klinisch nutzbarer Kontrasteffekt mit leberspezifischen Eigenschaften , 2000 .

[21]  T. Skotland,et al.  Hepatic clearance of Sonazoid perfluorobutane microbubbles by Kupffer cells does not reduce the ability of liver to phagocytose or degrade albumin microspheres , 2003, Cell and Tissue Research.

[22]  S. Kaul,et al.  Noninvasive Imaging of Myocardial Reperfusion Injury Using Leukocyte-Targeted Contrast Echocardiography , 2002, Circulation.

[23]  G. Schmid-Schönbein,et al.  Mechanism of parenchymal enhancement of the liver with a microbubble-based US contrast medium: an intravital microscopy study in rats. , 2002, Radiology.

[24]  P. Dayton,et al.  Acoustic radiation force in vivo: a mechanism to assist targeting of microbubbles. , 1999, Ultrasound in medicine & biology.

[25]  J. Kuszak,et al.  Development of inherently echogenic liposomes as an ultrasonic contrast agent. , 1996, Journal of pharmaceutical sciences.

[26]  Jonathan R. Lindner,et al.  Microbubbles in medical imaging: current applications and future directions , 2004, Nature Reviews Drug Discovery.

[27]  Raffi Bekeredjian,et al.  Augmentation of cardiac protein delivery using ultrasound targeted microbubble destruction. , 2005, Ultrasound in medicine & biology.

[28]  Nico de Jong,et al.  High-speed optical observations of contrast agent destruction. , 2005, Ultrasound in medicine & biology.

[29]  E. Wisner,et al.  The effect of size on the acoustic response of polymer-shelled contrast agents. , 2005, Ultrasound in medicine & biology.

[30]  D S Segar,et al.  Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial. , 1998, Journal of the American College of Cardiology.

[31]  Raffi Bekeredjian,et al.  Ultrasound-Targeted Microbubble Destruction Can Repeatedly Direct Highly Specific Plasmid Expression to the Heart , 2003, Circulation.

[32]  P. Roberson,et al.  Intracranial Clot Lysis With Intravenous Microbubbles and Transcranial Ultrasound in Swine , 2004, Stroke.

[33]  P. Dayton,et al.  A method for radiation-force localized drug delivery using gas-filled lipospheres , 2004, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[34]  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.

[35]  K. Tachibana,et al.  Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. , 1995, Circulation.

[36]  Feng Yan,et al.  BR1: A New Ultrasonographic Contrast Agent Based on Sulfur Hexafluoride-Filled Microbubbles , 1995, Investigative radiology.

[37]  S. Simon,et al.  Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of alphavbeta3-expressing cells. , 2004, Molecular imaging.

[38]  T. Marwick,et al.  What is the relationship between flow and function in diabetic cardiomyopathy? A quantitative study using contrast echo and strain rate imaging , 2004 .

[39]  D. Cosgrove,et al.  [Stimulated acoustic emissions with the ultrasound contrast medium levovist: a clinically useful contrast effect with liver-specific properties]. , 2000, RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin.

[40]  K W Ferrara,et al.  Direct video-microscopic observation of the dynamic effects of medical ultrasound on ultrasound contrast microspheres. , 1998, Investigative radiology.

[41]  J. Israelachvili,et al.  Impact of polymer tether length on multiple ligand-receptor bond formation. , 2001, Science.

[42]  Klaus Ley,et al.  Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[43]  D. McPherson,et al.  In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement. , 1999, Journal of the American College of Cardiology.

[44]  S. Kaul,et al.  Assessment of Endogenous and Therapeutic Arteriogenesis by Contrast Ultrasound Molecular Imaging of Integrin Expression , 2005, Circulation.

[45]  J. Xie,et al.  Pulsed high-intensity focused ultrasound enhances systemic administration of naked DNA in squamous cell carcinoma model: initial experience. , 2005, Radiology.

[46]  A. Klibanov,et al.  Ligand-carrying gas-filled microbubbles: ultrasound contrast agents for targeted molecular imaging. , 2005, Bioconjugate chemistry.

[47]  J. Hossack,et al.  Acoustic radiation force enhances targeted delivery of ultrasound contrast microbubbles: in vitro verification , 2005, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[48]  R. D. Venter,et al.  THE STABILITY OF GAS BUBBLES IN LIQUID‐GAS SOLUTIONS * , 1983 .

[49]  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.

[50]  E. Unger,et al.  Gene Delivery Using Ultrasound Contrast Agents , 2001, Echocardiography.

[51]  J. G. Miller,et al.  Targeting of ultrasound contrast material. An in vitro feasibility study. , 1997, Acta radiologica. Supplementum.

[52]  A. Klibanov,et al.  Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats. , 2002, Ultrasound in medicine & biology.

[53]  S. Kong,et al.  Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. , 2005, Journal of the American College of Cardiology.

[54]  L Weinert,et al.  Determination of Right Atrial and Right Ventricular Size by Two-Dimensional Echocardiography , 1979, Circulation.

[55]  E Krupinski,et al.  The use of a thrombus-specific ultrasound contrast agent to detect thrombus in arteriovenous fistulae. , 2000, Investigative radiology.

[56]  Anderson,et al.  Biodegradation and biocompatibility of PLA and PLGA microspheres. , 1997, Advanced drug delivery reviews.

[57]  K. Ley,et al.  Ultrasound Assessment of Inflammation and Renal Tissue Injury With Microbubbles Targeted to P-Selectin , 2001, Circulation.

[58]  J. Frangioni,et al.  In Vivo Tracking of Stem Cells for Clinical Trials in Cardiovascular Disease , 2004, Circulation.

[59]  T. Marwick,et al.  Real-time 3D echo increases feasibility of sequential echo follow-up in the real world - Reduction of test-retest variation of LV parameters , 2003 .

[60]  R Gramiak,et al.  Echocardiography of the aortic root. , 1968, Investigative radiology.

[61]  S. Kaul,et al.  Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. , 2002, Journal of the American College of Cardiology.

[62]  Jonathan R. Lindner,et al.  Noninvasive Assessment of Angiogenesis by Ultrasound and Microbubbles Targeted to &agr;v-Integrins , 2003, Circulation.

[63]  T. Porter,et al.  Transient myocardial contrast after initial exposure to diagnostic ultrasound pressures with minute doses of intravenously injected microbubbles. Demonstration and potential mechanisms. , 1995, Circulation.

[64]  M. Bednarski,et al.  Vascular‐targeted molecular imaging using functionalized polymerized vesicles , 2002, Journal of magnetic resonance imaging : JMRI.

[65]  Ji Song,et al.  Influence of injection site, microvascular pressure and ultrasound variables on microbubble-mediated delivery of microspheres to muscle. , 2002, Journal of the American College of Cardiology.

[66]  D. McPherson,et al.  Physical correlates of the ultrasonic reflectivity of lipid dispersions suitable as diagnostic contrast agents. , 2002, Ultrasound in medicine & biology.

[67]  Paul A. Dayton,et al.  Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents , 2004 .

[68]  C. Sigman,et al.  New science-based endpoints to accelerate oncology drug development. , 2005, European journal of cancer.

[69]  J. Bulte,et al.  Noninvasive monitoring of stem cell transfer for muscle disorders , 2004, Magnetic Resonance in Medicine.

[70]  Terry Matsunaga,et al.  Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. , 2005, Ultrasound in medicine & biology.

[71]  T. Skotland,et al.  Physical and biochemical characterization of Albunex, a new ultrasound contrast agent consisting of air‐filled albumin microspheres suspended in a solution of human albumin , 1994, Biotechnology and applied biochemistry.

[72]  P. Marmottant,et al.  Controlled vesicle deformation and lysis by single oscillating bubbles , 2003, Nature.

[73]  T. Sakuma,et al.  Simultaneous integrin alphavbeta3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty. , 2005, Cardiovascular research.

[74]  Michael Reinhardt,et al.  Evaluation of gas-filled microparticles and sonoporation as gene delivery system: feasibility study in rodent tumor models. , 2005, Radiology.

[75]  J. G. Miller,et al.  Targeting of ultrasound contrast material: selective imaging of microbubbles in vitro. , 1998, Academic radiology.

[76]  William R Wagner,et al.  Ultrasound Imaging of Acute Cardiac Transplant Rejection With Microbubbles Targeted to Intercellular Adhesion Molecule-1 , 2003, Circulation.

[77]  S. Kaul,et al.  Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles. , 2000, Circulation.

[78]  William R. Wagner,et al.  Modulating Targeted Adhesion of an Ultrasound Contrast Agent to Dysfunctional Endothelium , 2002, Annals of Biomedical Engineering.

[79]  A. Chait,et al.  Increase in Serum Amyloid A Evoked by Dietary Cholesterol Is Associated With Increased Atherosclerosis in Mice , 2004, Circulation.

[80]  K. Tachibana,et al.  Prototype therapeutic ultrasound emitting catheter for accelerating thrombolysis. , 1997, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[81]  Lawrence A Crum,et al.  Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. , 2005, Ultrasound in medicine & biology.

[82]  A. Klibanov,et al.  Detection of Individual Microbubbles of Ultrasound Contrast Agents: Imaging of Free-Floating and Targeted Bubbles , 2004, Investigative radiology.

[83]  K W Ferrara,et al.  Optical and acoustical dynamics of microbubble contrast agents inside neutrophils. , 2001, Biophysical journal.