Structure−Activity Relations of Nanolipoblockers with the Atherogenic Domain of Human Macrophage Scavenger Receptor A

Plourde, Nicole M.; Kortagere, Sandhya; Welsh, William J.; Moghe, Prabhas V.

doi:10.1021/bm8014522

Cited by 29 publications

(60 citation statements)

References 45 publications

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“…Targeting ligands can be immunogenic and may not be able to confer the broad-spectrum specificity to varying stages of plaque development seen with AM NPs (28). In contrast, the nanoscale presentation of AMs via the NPs elevates the net binding affinity of the AMs for SRs, leading to enhanced lesion retention and association with macrophages and activated endothelia (14). AM NP targeting may also occur because of the damaged endothelial lining covering plaques, enabling enhanced permeability and retention of nanoscale particles (6,29).…”

Section: Discussionmentioning

confidence: 99%

“…By decreasing lipid accumulation within the artery, local inflammation would be lower and result in an overall reduction in artery occlusion. In contrast to AM NP-treated mice, the histology of lesions in animals treated with control PS 14 PEG NPs did not show reduced lipid and inflammatory burden (SI Appendix, Fig. S9).…”

Section: Nps Lower Artery Occlusion By Reducing Lipid Accumulation Nmentioning

confidence: 93%

“…Using both in vitro and in silico models, AMs were found to competitively bind macrophage SRs, thus inhibiting modified lipid internalization and foam cell formation (13)(14)(15). When complexed around hydrophobic core solutes using kinetic fabrication techniques, the AMs form nanoparticles (NPs) that display resistance to unimer release in serum-rich environments (16,17).…”

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confidence: 99%

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Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Lewis¹,

Petersen²,

York³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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106

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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, sugarbased 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.atherosclerosis | nanomedicine | biomaterials | macrophages C ardiovascular disease is responsible for one in every three deaths in the United States (1). Chronically high circulating levels of low-density lipoprotein (LDL) deposit and undergo oxidation (oxLDL) within arterial walls, which consequently stimulates endothelial inflammation and recruitment of circulating monocytes (2). These recruited cells differentiate into macrophages that overexpress scavenger receptors (SR), which internalize oxLDL in an unregulated fashion, propagating the inflammatory cascade and leading to multifocal sites of neo-intimal plaques (3, 4). The prevalent cardiovascular therapeutics, which are focused on lowering circulating levels of LDL, are unable to directly target these developing atherosclerotic lesions (5).To address this unmet need, nanoassemblies have been designed to reach narrow vessels and abrogate the lipid deposition and atheroinflammatory phenomena that catalyze plaque establishment, growth, and ensuing acute or chronic cardiovascular events (6). Reports on recent advances in amphiphilic micelles require release of pharmacologic factors to counteract plaque aggravation and local delivery or the conjugation of targeting ligands to reach areas of atherosclerotic lesions (7-9). The ma...

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Section: Discussionmentioning

confidence: 99%

Section: Nps Lower Artery Occlusion By Reducing Lipid Accumulation Nmentioning

confidence: 93%

mentioning

confidence: 99%

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Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Lewis¹,

Petersen²,

York³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

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“…Previous research has shown the importance of downregulating macrophage scavenger receptors, as they exacerbate the inflammatory pathway in atherosclerosis [29]. As oxLDL uptake by scavenger receptor is also a critical step in the SMC proliferation pathway, we sought to specifically design AM systems to counteract oxidative stress leading to restenosis and thrombosis.…”

Section: Discussionmentioning

confidence: 99%

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

et al. 2016

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While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.

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“…It should be noted that pharmaceutical agents like apoA-I mimetic peptides, whose primary use is to raise serum levels of atheroprotective HDL and reverse atherosclerosis by lowering lipid loads within the vasculature, may also have beneficial effects by blocking SR-dependent macrophage adhesion, thereby facilitating egress of macrophages from the plaque (Neyen et al 2009). Similarly, a recent nanoscale approach blocking oxLDL binding to SRs in order to reduce foam cell formation has generated so-called nanolipoblockers functionalized with anionic groups, which mimic SR-A ligands, bind to the collagenous domain and show some promise in efficient out-competition of oxLDL (Plourde et al 2009). Comparable objectives have been reached for CD36, where a high-throughput screen for small-molecule inhibitors of modified LDL uptake identified two promising leads with micromolar IC 50 that may antagonize foam cell formation (Xu et al 2010).…”

Section: Discussionmentioning

confidence: 99%