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WIREs Nanomed Nanobiotechnol
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Polymer‐based therapeutics: nanoassemblies and nanoparticles for management of atherosclerosis

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Abstract Coronary arterial disease, one of the leading causes of adult mortality, is triggered by atherosclerosis. A disease with complex etiology, atherosclerosis results from the progressive long‐term combination of atherogenesis, the accumulation of modified lipoproteins within blood vessel walls, along with vascular and systemic inflammatory processes. The management of atherosclerosis is challenged by the localized flare‐up of several multipronged signaling interactions between activated monocytes, atherogenic macrophages and inflamed or dysfunctional endothelial cells. A new generation of approaches is now emerging founded on multifocal, targeted therapies that seek to reverse or ameliorate the atheroinflammatory cascade within the vascular intima. This article reviews the various classes and primary examples of bioactive configurations of nanoscale assemblies. Of specific interest are polymer‐based or polymer‐lipid micellar assemblies designed as multimodal receptor‐targeted blockers or drug carriers whose activity can be tuned by variations in polymer hydrophobicity, charge, and architecture. Also reviewed are emerging reports on multifunctional nanoassemblies and nanoparticles for improved circulation and enhanced targeting to atheroinflammatory lesions and atherosclerotic plaques. WIREs Nanomed Nanobiotechnol 2011 3 400–420 DOI: 10.1002/wnan.145 This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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Key cellular and molecular interactions that trigger the onset of atherosclerosis. Hyperlipidemia and intimal retention of LDL within the arterial wall initiates a cascade of events leading to LDL oxidation and subsequent inflammatory response. Upregulated cell adhesion molecules [selectins (a) and IgG‐type (b)] promote the recruitment of circulating monocytes and increase the permeability of endothelium facilitating more LDL transport to the extravascular space. Endothelial cells and monocytes differentiated into macrophages internalize oxLDL through scavenger receptors [LOX‐1 (c), SRA‐1, and CD36 (d)]. Unregulated oxLDL uptake by scavenger receptors in macrophages leads to the formation of ‘foam cells' (e). The buildup of oxidized lipids triggers the secretion of a range of cytokines and engenders a more inflammatory phenotype within all vascular cells. Compromised endothelia expose basement membrane to thrombosis, forming fibrin clots (f). Further, to fulfill the increased metabolic demand of the cells in growing plaques, new blood vessels start to form in the media and extend into the intima (g). As the lesion progresses, the endothelium becomes dysfunctional and smooth muscle cells start to migrate, making the lesion a dynamic mass protruding inside the lumen of the vessel that reduces blood flow to vital organs downstream.

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(a) Chemical structure of the unimers with variable X‐group (targeting peptide, fluorophore or drug molecule) and 3D representation of mixed micelles combining targeting, tracking, and therapeutic modalities. (b) Localization of fibrin targeting peptide conjugated micelles in atherosclerotic plaques. Serial cross sections stained with endothelial (CD31), macrophage (CD68) and fibrin(ogen) specific antibodies illustrate that micelles bind to entire surface of the plaque and penetrate under endothelium in the shoulder region. (Reprinted with permission from Ref 59. Copyright 2009 National Academy of Sciences)

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(a) Idealized representation of the structures and interactions between the amphiphilic polymer and SR‐A1 receptor that were utilized in molecular modeling simulations. (b) Schematic representation of the docked interactions of SR‐A1 collagen‐like domain homology model residues (as seen in the colored circles) with 1cM, 1cP, 0cM, and PEG‐COOH. Residue characteristics are illustrated through color: purple: polar, green: hydrophobic, blue border: basic, and red border: acidic. (c) Binding energy values calculated from polymer models docked to SR‐A1 collagen‐like domain homology model. (Reprinted with permission from Ref 42. Copyright 2010 American Chemical Society)

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Structure function relationship of the bioactive nanopolymers designed to reduce oxLDL uptake in macrophages. Degree of oxLDL inhibition with serum‐free and serum conditions in the presence of polymers show the importance of carrier design criteria for the individual unimers that form micelles. (a) Schematic represantations and chemical structures of polymeric unimers; (b) effect of amphiphilicity and anionic charge; (c) effect of anionic charge location; (d) effect of number and rotational freedom of the anionic charge located in the hydrophobic domain; (e) micrographs showing the internalization of BODIPY labeled oxLDL in the absence or presence of 1cM. (Reprinted with permission from Ref 39. Copyright 2010 Elsevier, Ltd.)

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Targetable cell‐surface receptors for diagnostic and theraputic applications of atherosclerosis. See text for details.

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Unimer to micelle transition above the critical micelle concentration (CMC) in the presence of a therapeutic or diagnostic agent. Blue represents hydrophilic polymer.

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Nanoassemblies for the management or diagnosis of atherosclerosis can be classified into four broad categories: (a) bioactive micelle with inherent therapeutic capabilities; (b) drug loaded micelle with targeting ligands for cell‐specific delivery; (c) polymer modified nanoparticle (gold, super paramagnetic iron oxide, quantum dots, etc.) for imaging applications; (d) mixed micelles with both therapeutic and diagnostic capabilities. Blue: hydrophilic polymer and red: hydrophobic polymer or lipid.

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Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease

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