Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remai...

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Vydáno v:Proceedings of the National Academy of Sciences - PNAS Ročník 112; číslo 9; s. 2693
Hlavní autoři: Lewis, Daniel R, Petersen, Latrisha K, York, Adam W, Zablocki, Kyle R, Joseph, Laurie B, Kholodovych, Vladyslav, Prud'homme, Robert K, Uhrich, Kathryn E, Moghe, Prabhas V
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 03.03.2015
Témata:
Animals
Atherosclerosis - drug therapy
Atherosclerosis - genetics
Atherosclerosis - metabolism
Atherosclerosis - pathology
Carbohydrates
CD36 Antigens - genetics
CD36 Antigens - metabolism
Humans
Hyperplasia - genetics
Hyperplasia - metabolism
Hyperplasia - pathology
Lipids
Macrophages - metabolism
Macrophages - pathology
Mice
Mice, Knockout
Nanoparticles
Neointima - genetics
Neointima - metabolism
Neointima - pathology
Oxidation-Reduction
Plaque, Atherosclerotic - blood
Plaque, Atherosclerotic - drug therapy
Plaque, Atherosclerotic - genetics
Plaque, Atherosclerotic - metabolism
Plaque, Atherosclerotic - pathology
Scavenger Receptors, Class A - genetics
Scavenger Receptors, Class A - metabolism
atherosclerosis
nanomedicine
macrophages
biomaterials
ISSN:1091-6490, 1091-6490
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Shrnutí:Atherosclerosis, the build-up of occlusive, lipid-rich plaques in arterial walls, is a focal trigger of chronic coronary, intracranial, and peripheral arterial diseases, which together account for the leading causes of death worldwide. Although the directed treatment of atherosclerotic plaques remains elusive, macrophages are a natural target for new interventions because they are recruited to lipid-rich lesions, actively internalize modified lipids, and convert to foam cells with diseased phenotypes. In this work, we present a nanomedicine platform to counteract plaque development based on two building blocks: first, at the single macrophage level, sugar-based amphiphilic macromolecules (AMs) were designed to competitively block oxidized lipid uptake via scavenger receptors on macrophages; second, for sustained lesion-level intervention, AMs were fabricated into serum-stable core/shell nanoparticles (NPs) to rapidly associate with plaques and inhibit disease progression in vivo. An AM library was designed and fabricated into NP compositions that showed high binding and down-regulation of both MSR1 and CD36 scavenger receptors, yielding minimal accumulation of oxidized lipids. When intravenously administered to a mouse model of cardiovascular disease, these AM NPs showed a pronounced increase in lesion association compared with the control nanoparticles, causing a significant reduction in neointimal hyperplasia, lipid burden, cholesterol clefts, and overall plaque occlusion. Thus, synthetic macromolecules configured as NPs are not only effectively mobilized to lipid-rich lesions but can also be deployed to counteract atheroinflammatory vascular diseases, highlighting the promise of nanomedicines for hyperlipidemic and metabolic syndromes.
Bibliografie:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1424594112