Carbohydrate composition of amphiphilic macromolecules influences physicochemical properties and binding to atherogenic scavenger receptor A

Hehir, Sarah; Plourde, Nicole M.; Gu, Li; Poree, Dawanne E.; Welsh, William J.; Moghe, Prabhas V.; Uhrich, Kathryn E.

doi:10.1016/j.actbio.2012.07.022

Cited by 28 publications

(33 citation statements)

References 39 publications

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“…At the higher concentrations, the phosphonate-AM micelles may provide enhanced binding to the cationic MSR1 and CD36 residues, thereby inhibiting oxLDL internalization and moderating scavenger receptor expression [36, 42]. In previous work, anionic AMs with a greater net negative charge were more efficacious in counteracting macrophage oxLDL uptake in silico and in vitro due to their favorable binding energies [25–27]. This study demonstrates that similar principles can be applied to repress SMC proliferation through scavenger receptor interactions.…”

Section: Discussionmentioning

confidence: 99%

“…The critical micelle concentration (CMC) of 1pM and 1cM were determined as previously described [27]. In brief, AMs were dissolved in HPLC grade H 2 O and diluted to a series of concentrations ranging from 1 × 10 −3 to 1 × 10 −10 M. Separately, a stock solution of pyrene was prepared in HPLC grade acetone (5 × 10 −6 M) and 0.5 mL of this solution was added to a series of vials.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

et al. 2016

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“…AMs were synthesized as previously described (19,26,34,35) and fabricated into kinetically assembled fluorescent NPs via flash nanoprecipitation (16,17). NP shell structures are depicted in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…AMs with varying charge, hydrophobicity, and stereochemistry ( Fig. 2A) were synthesized, guided by the hypothesis that these are critical features for SR binding (19). These AMs were then used as graded "shells" to engineer a library of AM NPs using flash nanoprecipitation around a common hydrophobic core solute (Fig.…”

Section: Am Nps With Comprehensive Atheroprotective Profiles Can Bementioning

confidence: 99%

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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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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“…To assess the influence of molecular conformation on bioactivity [29], the double bond that restricted rotational flexibility was introduced to the backbone and T(12-O)P5 unsat was synthesized. Ag 2 O served as both catalyst for ether formation [28] and oxidizing reagent [30] in the first step.…”

Section: Resultsmentioning

confidence: 99%

Micellar and structural stability of nanoscale amphiphilic polymers: Implications for anti-atherosclerotic bioactivity

Zhang

Welsh

et al. 2016

Biomaterials

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Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies.

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Carbohydrate composition of amphiphilic macromolecules influences physicochemical properties and binding to atherogenic scavenger receptor A

Cited by 28 publications

References 39 publications

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Micellar and structural stability of nanoscale amphiphilic polymers: Implications for anti-atherosclerotic bioactivity

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