Molecular and Cellular Imaging with Targeted Contrast Ultrasound

Molecular imaging is an expanding field that involves the noninvasive detection of cellular and molecular mediators of disease using a range of imaging modalities. Molecular imaging using contrast-enhanced ultrasound relies on the detection of novel site-targeted ultrasound contrast agents. Gas-filled encapsulated microbubbles provide a sensitive and high-resolution ultrasound contrast agent, and site-targeted imaging is facilitated by the manipulation of the shell surface of these microbubbles. Nonmicrobubble agents such as immunoliposomes and small nanoemulsion agents have also been developed for targeting purposes. These contrast agents are retained within regions of a specific pathophysiological process, thereby allowing noninvasive phenotypic characterization of tissue. Since microbubbles are pure intravascular tracers, they provide an optimal agent to assess molecular processes occurring on the vascular endothelial surface. Accordingly, the pathologic states that have been targeted include inflammation, angiogenesis associated with ischemia and neoplasms, and thrombus formation. This review describes: 1) the potential clinical and research uses for targeted imaging; 2) strategies that have been employed for the creation of site-targeted ultrasound contrast agents; 3) the unique challenges for imaging targeted ultrasound contrast agents; and 4) initial results and experience in the imaging of molecular events in animal models of disease.

[1]  In vitro characterization of liposomes and Optison by acoustic scattering at 3.5 MHz. , 2003, Ultrasound in medicine & biology.

[2]  S. Kaul,et al.  Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin- and complement-mediated adherence to activated leukocytes. , 2000, Circulation.

[3]  A R Jayaweera,et al.  Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. , 1998, Circulation.

[4]  F. Blankenberg,et al.  Annexin-V imaging for noninvasive detection of cardiac allograft rejection , 2001, Nature Medicine.

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

[6]  AndrewHamilton,et al.  Left Ventricular Thrombus Enhancement After Intravenous Injection of Echogenic Immunoliposomes , 2002 .

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

[8]  M. S. Plesset,et al.  On the stability of gas bubbles in liquid-gas solutions , 1950 .

[9]  Stasia A. Anderson,et al.  Magnetic resonance contrast enhancement of neovasculature with αvβ3‐targeted nanoparticles , 2000 .

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

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

[12]  S. Targan,et al.  Inflammatory Bowel Disease: From Bench to Bedside , 1994 .

[13]  S. Kaul,et al.  Noninvasive Ultrasound Imaging of Inflammation Using Microbubbles Targeted to Activated Leukocytes , 2000, Circulation.

[14]  J. G. Miller,et al.  In vitro characterization of a novel, tissue-targeted ultrasonic contrast system with acoustic microscopy. , 1998, The Journal of the Acoustical Society of America.

[15]  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.

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

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

[18]  E. Unger,et al.  In vitro studies of a new thrombus-specific ultrasound contrast agent. , 1998, The American journal of cardiology.

[19]  D. McPherson,et al.  Left Ventricular Thrombus Enhancement After Intravenous Injection of Echogenic Immunoliposomes: Studies in a New Experimental Model , 2002, Circulation.

[20]  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.

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

[22]  J. G. Miller,et al.  In vivo molecular imaging of stretch-induced tissue factor in carotid arteries with ligand-targeted nanoparticles. , 2000, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[23]  G. Beller,et al.  Assessment of Myocardial Inflammation Produced by Experimental Coronary Occlusion and Reperfusion With 99mTc-RP517, a New Leukotriene B4 Receptor Antagonist That Preferentially Labels Neutrophils In Vivo , 2002, Circulation.

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

[25]  David A. Cheresh,et al.  Definition of Two Angiogenic Pathways by Distinct αv Integrins , 1995, Science.

[26]  M Schwaiger,et al.  Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[27]  S A Wickline,et al.  Novel MRI Contrast Agent for Molecular Imaging of Fibrin: Implications for Detecting Vulnerable Plaques , 2001, Circulation.

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

[29]  Lars Hoff,et al.  Acoustic properties of shell-encapsulated, gas-filled ultrasound contrast agents , 1996, 1996 IEEE Ultrasonics Symposium. Proceedings.

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

[31]  B. E. Noltingk,et al.  Cavitation produced by Ultrasonics , 1950 .

[32]  J. G. Miller,et al.  A novel site-targeted ultrasonic contrast agent with broad biomedical application. , 1996, Circulation.

[33]  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.

[34]  S A Wickline,et al.  Molecular imaging of stretch-induced tissue factor expression in carotid arteries with intravascular ultrasound. , 2000, Investigative radiology.

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

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

[37]  M. Bednarski,et al.  Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. , 1998, Nature medicine.

[38]  S. Kaul,et al.  Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. , 1996, Journal of the American College of Cardiology.

[39]  F. Sellke,et al.  Therapeutic angiogenesis for coronary artery disease , 2002, Current treatment options in cardiovascular medicine.

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

[41]  K. Ley,et al.  Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling. , 1995, Journal of immunology.

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

[43]  P. Burns.  Harmonic imaging with ultrasound contrast agents. , 1996, Clinical radiology.

[44]  Jiri Sklenar,et al.  Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration. , 2002, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[45]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[46]  N de Jong,et al.  Absorption and scatter of encapsulated gas filled microspheres: theoretical considerations and some measurements. , 1992, Ultrasonics.

[47]  K. Ley,et al.  Molecular mechanisms of leukocyte recruitment in the inflammatory process. , 1996, Cardiovascular research.

[48]  W. Schaper,et al.  Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. , 1998, The Journal of clinical investigation.

[49]  Charles T. Lancée,et al.  Higher harmonics of vibrating gas-filled microspheres. Part one: simulations , 1994 .

[50]  David A. Cheresh,et al.  Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging , 1998, Nature Medicine.