Abstract
Inflammation plays an important role in the development of atherosclerosis. The endothelium is an active organ that forms a barrier between the circulation and the arterial wall. In response to pro-atherogenic factors, the endothelium is induced to become an adhesive and pro-thrombotic surface. A range of molecular markers associated with early and late changes in atherogenesis have been identified in the endothelium. Those pathological changes in the endothelium are potential targets for early detection of atherosclerosis and may precede advanced changes that can be detected by conventional imaging modalities, such as coronary angiography. Acoustically active contrast agents have been widely used for clinical applications such as enhancing cardiac chamber definition and measuring myocardial perfusion in diagnostic ultrasound imaging. In the context of molecular imaging, those agents are pure intravascular tracers and are ideally suited for interrogating the expression of molecular markers on the endothelium. Studies have demonstrated how microbubbles can detect inflammation by means of the interactions between their lipid shell components and leukocytes that co-localize on the surface of inflamed endothelium. More sophisticated acoustically active targeting agents, however, involve the incorporation of high-affinity peptides or antibodies into their lipid shell that highlight inflammatory markers, thrombosis, and neovascularization in the arterial wall in atherosclerotic animal models. Before those agents can be widely used in clinical practice, they will require further refinements to reduce immunogenicity of targeting ligands, minimize toxicity of lipid shell components, and improve acoustic stability after intravenous administration. The most challenging aspect of this research is, however, the identification of clinically relevant markers that can accurately predict the presence and progression of atherosclerosis.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Alkan-Onyuksel, H., Demos, S. M., et al., 1996. Development of inherently echogenic liposomes as an ultrasonic contrast agent. J Pharm Sci 85,5, 486–490.
Barker, S.G., Talbert, A., et al., 1993. Arterial intimal hyperplasia after occlusion of the adventitial vasa vasorum in the pig. Arterioscler Thromb 13,1, 70–77.
Basalyga, D.M., Wagner, W.R., et al., 1998. Albumin microbubbles adhere to exposed extracellular matrix of perfused whole vessels. Circulation 98, I-290.
Booth, R.F., Martin, J.F., et al., 1989. Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation. Atherosclerosis 76,2–3, 257–268.
Bredehorst, R., Ligler, F.S., et al., 1986. Effect of covalent attachment of immunoglobulin fragments on liposomal integrity. Biochemistry 25,19, 5693–5698.
Chen, M., Masaki, T., et al., 2002. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther 95,1, 89–100.
Cybulsky, M.I., Gimbrone, M.A., Jr., 1991. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251,4995, 788–791.
Demos, S.M., Alkan-Onyuksel, H., et al., 1999. In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement. J Am Coll Cardiol 33,3, 867–875.
Demos, S.M., Dagar, S., et al., 1998. In vitro targeting of acoustically reflective immunoliposomes to fibrin under various flow conditions. J Drug Target 5,6, 507–518.
Demos, S.M., Onyuksel, H., et al., 1997. In vitro targeting of antibody-conjugated echogenic liposomes for site-specific ultrasonic image enhancement. J Pharm Sci 86,2, 167–171.
Demos, S.M., Ramani, K., et al., 1996. Targeted acoustic liposomes for atherosclerotic enhancement during intravascular and transvascular ultrasonic imaging. Circulation 94, I-209.
Fadok, V.A., Voelker, D.R., et al., 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148,7, 2207–2216.
Fisher, N.G., Christiansen, J.P., et al., 2002. Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. J Am Coll Cardiol 40,4, 811–819.
Fu, X., Kassim, S.Y., et al., 2001. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 276,44, 41279–41287.
Galis, Z.S., Khatri, J.J. 2002. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90,3, 251–262.
Geng, Y.J., Henderson, L.E., et al., 1997. Fas is expressed in human atherosclerotic intima and promotes apoptosis of cytokine-primed human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 17,10, 2200–2208.
Glagov, S., Weisenberg, E., et al., 1987. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316,22, 1371–1375.
Gradus-Pizio, I., Bigelow, B., et al., 2002. The role of adventitia in coronary atherosclerosis: results of echocardiographic imaging of the left anterior descending coronary artery. J Am Coll Cardiol 39, 246A.
Hamilton, A., Benzuly, K., et al., 2002a. Adventitial thickening in non-occlusive atherosclerosis determined by high resolution echocardiographic imaging of the left anterior descending coronary artery. J Invest Med 50, 235A.
Hamilton, A., Rabbat, M., et al., 2002b. A physiologic flow chamber model to define intravascular ultrasound enhancement of fibrin using echogenic liposomes. Invest Radiol 37,4, 215–221.
Hamilton, A.J., Huang, S.L., et al., 2004. Intravascular ultrasound molecular imaging of atheroma components in vivo. J Am Coll Cardiol 43,3, 453–460.
Heath, T.D., Montgomery, J.A., et al., 1983. Antibody-targeted liposomes: increase in specific toxicity of methotrexate-gamma-aspartate. Proc Natl Acad Sci U S A 80,5, 1377–1381.
Herrmann, J., Lerman, L.O., et al., 2001. Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia. Cardiovasc Res 51,4, 762–766.
Houston, P., Goodman, J., et al., 2001. Homing markers for atherosclerosis: applications for drug delivery, gene delivery and vascular imaging. FEBS Lett 492,1–2, 73–77.
Huang, S.L., Hamilton, A.J., et al., 2001. Improving ultrasound reflectivity and stability of echogenic liposomal dispersions for use as targeted ultrasound contrast agents. J Pharm Sci 90,12, 1917–1926.
Kasper, H.U., Schmidt, A., et al., 1996. Expression of the adhesion molecules ICAM, VCAM, and ELAM in the arteriosclerotic plaque. Gen Diagn Pathol 141,5–6, 289–294.
Klibanov, A., Gu, H., et al., 1999. Attachment of ligands to gas-filled microbubbles via PEG spacer and lipid residues anchored at the interface. Controlled Release Society, Boston.
Klibanov, A.L., 1999. Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging. Adv Drug Deliv Rev 37,1–3, 139–157.
Klibanov, A.L., Hughes, M.S., et al., 1997. Targeting of ultrasound contrast material. An in vitro feasibility study. Acta Radiol Suppl 412, 113–120.
Klibanov, A.L., Hughes, M.S., et al., 1998. Targeting of ultrasound contrast material: selective imaging of microbubbles in vitro. Acad Radiol 5,Suppl 1, S243–S246.
Klibanov, A.L., Rasche, P.T., et al., 2002. Detection of individual microbubbles of an ultrasound contrast agent: fundamental and pulse inversion imaging. Acad Radiol 9,Suppl 2, S279–S281.
Klibanov, A.L., Rasche, P.T., et al., 2004. Detection of individual microbubbles of ultrasound contrast agents: imaging of free-floating and targeted bubbles. Invest Radiol 39,3 187–195.
Kolodgie, F.D., Petrov, A., et al., 2003. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108,25, 3134–3139.
Korpanty, G., Grayburn, P.A., et al., 2005. Targeting vascular endothelium with avidin microbubbles. Ultrasound Med Biol 31,9, 1279–1283.
Kranzhofer, R., Clinton, S.K., et al., 1996. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res 79,2, 286–294.
Kunjathoor, V.V., Febbraio, M., et al., 2002. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem 277,51, 49982–49988.
Kwon, H.M., Sangiorgi, G., et al., 1998. Enhanced coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Clin Invest 101,8, 1551–1556.
Lanza, G.M., Wallace, K.D., et al., 1996. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation 94,12, 3334–3340.
Leong-Poi, H., Christiansen, J., et al., 2003. Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to alpha(v)-integrins. Circulation 107,3, 455–460.
Lindner, J.R., Coggins, M.P., et al., 2000a. Microbubble persistence in the microcirculation during ischemia/reperfusion and inflammation is caused by integrin-and complement-mediated adherence to activated leukocytes. Circulation 101,6, 668–675.
Lindner, J.R., Dayton, P.A., et al., 2000b. Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles. Circulation 102,5, 531–538.
Lindner, J.R., Ismail, S., et al., 1998. Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage. Circulation 98,20, 2187–2194.
Lindner, J.R., Song, J., et al., 2001. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation 104,17, 2107–2112.
Liu, C., Bhattacharjee, G., et al., 2003. In vivo interrogation of the molecular display of atherosclerotic lesion surfaces. Am J Pathol 163,5, 1859–1871.
Martin, F.J., Heath, T.D., et al., 1990. Covalent attachment of proteins to liposomes. New York, IRL Press.
McPherson, D.D., Sirna, S.J., et al., 1991. Coronary arterial remodeling studied by high-frequency epicardial echocardiography: an early compensatory mechanism in patients with obstructive coronary atherosclerosis. J Am Coll Cardiol 17,1, 79–86.
Moreno, P.R., Purushothaman, K.R., et al., 2002. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implications for plaque vulnerability. Circulation 105,21, 2504–2511.
O’Rourke, R., O’Gara, P., et al., 2004. Diagnosis and management of patients with chronic ischemic heart disease. Hurst’s the heart. V. Fuster, R. Alexander and R. O’Rourke. New York, McGraw-Hill, 1465–1494.
Schumann, P.A., Christiansen, J.P., et al., 2002. Targeted-microbubble binding selectively to GPIIb IIIa receptors of platelet thrombi. Invest Radiol 37,11, 587–593.
Shaw, P.X., Horkko, S., et al., 2001. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler Thromb Vasc Biol 21,8, 1333–1339.
Takeuchi, M., Ogunyankin, K., et al., 1999. Enhanced visualization of intravascular and left atrial appendage thrombus with the use of a thrombus-targeting ultrasonographic contrast agent (MRX-408A1): In vivo experimental echocardiographic studies. J Am Soc Echocardiogr 12,12, 1015–1021.
Unger, E.C., Lund, P.J., et al., 1992. Nitrogen-filled liposomes as a vascular US contrast agent: preliminary evaluation. Radiology 185,2, 453–456.
Unger, E.C., McCreery, T., et al., 1998a. MRX 501: a novel ultrasound contrast agent with therapeutic properties. Acad Radiol 5,Suppl 1, S247–S249.
Unger, E.C., McCreery, T.P., et al., 1998b. Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent. Invest Radiol 33,12, 886–892.
Unger, E.C., McCreery, T.P., et al., 1998c. In vitro studies of a new thrombus-specific ultrasound contrast agent. Am J Cardiol 81,12A, 58G-61G.
van der Loo, B., Martin J.F., 1997. The adventitia, endothelium and atherosclerosis. Int J Microcirc Clin Exp 17,5, 280–288.
van der Wal, A.C., Becker, A.E., et al., 1993. Medial thinning and atherosclerosis– evidence for involvement of a local inflammatory effect. Atherosclerosis 103,1, 55–64.
Villanueva, F.S., Jankowski, R.J., et al., 1998. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells. Circulation 98,1, 1–5.
Weller, G.E., Lu, E., et al., 2003. Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation 108,2, 218–224.
Wu, Y., Unger, E.C., et al., 1998. Binding and lysing of blood clots using MRX-408. Invest Radiol 33,12, 880–885.
Yasu, T., Greener, Y., et al., 2005. Activated leukocytes and endothelial cells enhance retention of ultrasound contrast microspheres containing perfluoropropane in inflamed venules. Int J Cardiol 98,2, 245–252.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Kee, P.H., McPherson, D.D. (2008). Use of Acoustically Active Contrast Agents in Imaging of Inflammation and Atherosclerosis. In: Bulte, J.W., Modo, M.M. (eds) Nanoparticles in Biomedical Imaging. Fundamental Biomedical Technologies, vol 102. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72027-2_17
Download citation
DOI: https://doi.org/10.1007/978-0-387-72027-2_17
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-72026-5
Online ISBN: 978-0-387-72027-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)