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WIREs Nanomed Nanobiotechnol
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Anti‐angiogenic perfluorocarbon nanoparticles for diagnosis and treatment of atherosclerosis

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Abstract Complementary developments in nanotechnology, genomics, proteomics, molecular biology and imaging offer the potential for early, accurate diagnosis. Molecularly‐targeted diagnostic imaging agents will allow noninvasive phenotypic characterization of pathologies and, therefore, tailored treatment close to the onset. For atherosclerosis, this includes anti‐angiogenic therapy with specifically‐targeted drug delivery systems to arrest the development of plaques before they impinge upon the lumen. Additionally, monitoring the application and effects of this targeted therapy in a serial fashion will be important. This review covers the specific application of ανβ3‐targeted anti‐angiogenic perfluorocarbon nanoparticles in (1) the detection of molecular markers for atherosclerosis, (2) the immediate verification of drug delivery with image‐based prediction of therapy outcomes, and (3) the serial, noninvasive observation of therapeutic efficacy Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease

Generalized paradigm for targeted nanoparticle contrast agents. The nanoparticle core provides a framework onto which volumes of the targeting system, imaging and therapeutic agents can be placed. Nanoscaled agents, with their high surface‐area‐to‐volume ratio, provide the amplification strategies that permit molecular imaging to be feasible when targeting sparse epitopes. (Reprinted, with permission, from Ref. 57. Copyright 2003.).

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Molecular imaging of therapy response to anti‐angiogenic nanoparticles. MR imaging of hyperlipidemic rabbit aorta (as in Figure 4) showing the false‐colored overlay of signal enhancement as a result of ανβ3 targeted paramagnetic nanoparticles at time of treatment (top row). On follow‐up imaging 1 week later (bottom row), the subject receiving drug‐laden nanoparticles (left) shows marked reduction in the atherosclerosis‐related angiogenesis compared to the subject receiving no drug (right). (Reprinted, with permission, from Ref. 114. Copyright 2006.).

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Schematic representation of ‘contact facilitated drug delivery.’ Phospholipids and drug within the perfluorocarbon nanoparticle surfactant exchange with lipids of the target membrane through a convection process rather than diffusion, as is common among other targeted systems. Without the stable membrane contact, enabled through specific binding, drug is not released from the particle. (Reprinted, with permission, from Ref. 106. Copyright 2004.).

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19F MR spectroscopy and imaging of liquid perfluorocarbon nanoparticles bound to in vitro fibrin clots. The four 19F spectra (a) acquired from the corresponding four clots (b) demonstrate the changing concentrations of the two different nanoparticle species applied. The three columns of 19F images (b), which have no proton background, represent three ‘weightings’ of the same four clots. Without selectivity (NS), all clots have high signal. Employing a species‐selective excitation allows independent visualization of the bound 15‐crown‐5 ether (CE) or perfluorooctyl bromide (PFOB) nanoparticles. (Reprinted, with permission, from Ref. 36. Copyright 2006 Springer.).

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In vivo MR images of hyperlipidemic rabbit aorta. (a) The ανβ3‐targeted nanoparticles cause heterogeneous signal enhancement along the entire vessel wall. (b) Transverse images before (pre) and after (post) nanoparticles, after segmentation of the vessel wall (segmented), and the final images (enhancement) with color encoding of the percent enhancement resulting from the contrast agent bound to the marker of angiogenesis in this model of early atherosclerosis. (Reprinted, with permission, from Ref. 77. Copyright 2003.).

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Fibrin‐targeted paramagnetic nanoparticles. A scanning electron micrograph (a) shows the fibrin tendrils within a clot. Targeted nanoparticles densely decorate the fibrin (b), bringing large volumes of imaging agent (gadolinium chelates) per binding site. The effect, in this canine model (c), is a marked enhancement (arrow) as compared to the control clot in the contralateral vein. (Reprinted, with permission, from Ref. 75. Copyright 2001.).

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Ultrasound imaging of femoral artery thrombus before (a) and after (b) exposure to targeted perfluorocarbon nanoparticles. (a) While the transmural electrode (anode) and the vessel wall boundaries of the femoral artery are clearly delineated with a 7.5 MHz linear‐array, focused transducer, the acute thrombus is poorly visualized. (b) After exposure to the targeted emulsion, the thrombus is easily visualized. (Reprinted, with permission, from Ref. 37. Copyright 1996.).

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