Amphiphilic Scorpion-like Macromolecules:  Design, Synthesis, and Characterization

Tian, Lu; Yam, Larry; Zhou, Nan; Tat, Henry; Uhrich, Kathryn E.

doi:10.1021/ma030411a

Cited by 76 publications

(154 citation statements)

References 51 publications

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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%

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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104

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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: Methodsmentioning

confidence: 99%

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Lewis¹,

Petersen²,

York³

et al. 2015

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

Self Cite

104

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“…Novel amphiphilic scorpion-like macromolecules (AScMs; Scheme 15) were designed comprising acylation of mucic acid with acyl chlorides of varying chain lengths as the branched hydrophobic domains whereas PEG as hydrophilic domains (131,132). Low CMC values (10 j5 Y10 j7 mol/l) and small particle sizes (10Y20 nm) of AScMs were observed.…”

Section: Hyperbranched Polymersmentioning

confidence: 99%

Polymer Architecture and Drug Delivery

2006

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Polymers occupy a major portion of materials used for controlled release formulations and drug-targeting systems because this class of materials presents seemingly endless diversity in topology and chemistry. This is a crucial advantage over other classes of materials to meet the ever-increasing requirements of new designs of drug delivery formulations. The polymer architecture (topology) describes the shape of a single polymer molecule. Every natural, seminatural, and synthetic polymer falls into one of categorized architectures: linear, graft, branched, cross-linked, block, star-shaped, and dendron/dendrimer topology. Although this topic spans a truly broad area in polymer science, this review introduces polymer architectures along with brief synthetic approaches for pharmaceutical scientists who are not familiar with polymer science, summarizes the characteristic properties of each architecture useful for drug delivery applications, and covers recent advances in drug delivery relevant to polymer architecture.

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“…Literature reported polymeric micelle cmc values are usually in the range of 10 −5 to 10 −6 M [10,11]. However, the AScM polymeric micelles, especially the mucic acid-derivatized AScM polymeric micelles distinguish themselves with their extremely low cmc values (10 −6 -10 −7 M) [23], which is expected to significantly enhance the solution stability of the polymeric micelles. The ASMs, as represented in Fig.…”

Section: Introductionmentioning

confidence: 99%

“…A series of AScMs have been synthesized that differ in both the hydrophobic and the hydrophilic domains [23,24]. This manuscript focuses only on the hydrophobic domains as they appear to contribute most significantly to properties of polymeric micelles.…”

Section: Introductionmentioning

confidence: 99%

Amphiphilic Scorpion-like Macromolecules: Design, Synthesis, and Characterization

Cited by 76 publications

References 51 publications

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Polymer Architecture and Drug Delivery

Novel amphiphilic macromolecules and their in vitro characterization as stabilized micellar drug delivery systems

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