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 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.

Nanoscale amphiphilic macromolecules with variable lipophilicity and stereochemistry modulate inhibition of oxidized low-density lipoprotein uptake.

Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability.

Coarse grained molecular dynamics of engineered macromolecules for the inhibition of oxidized low-density lipoprotein uptake by macrophage scavenger receptors.

Atherosclerosis is a condition resulting from the accumulation of oxidized low-density lipoproteins (oxLDLs) in arterial walls. Previously developed macromolecules consisting of alkyl chains and polyethylene glycol (PEG) on a mucic acid backbone, termed nanolipoblockers (NLBs) are hypothesized to mitigate the uptake of oxLDL by macrophage scavenger receptors. In this work, we developed a coarse grained model to characterize the interactions between NLBs with a segment of human scavenger receptor A (SR-A), a key receptor domain that regulates cholesterol uptake and foam cell conversion of macrophages, and studied NLB ability to block oxLDL uptake in PBMC macrophages.

Impact of ionizing radiation on physicochemical and biological properties of an amphiphilic macromolecule.

An amphiphilic macromolecule (AM) was exposed to ionizing radiation (both electron beam and gamma) at doses of 25 kGy and 50 kGy to study the impact of these sterilization methods on the physicochemical properties and bioactivity of the AM. Proton nuclear magnetic resonance and gel permeation chromatography were used to determine the chemical structure and molecular weight, respectively. Size and zeta potential of the micelles formed from AMs in aqueous media were evaluated by dynamic light scattering.

Kinetically assembled nanoparticles of bioactive macromolecules exhibit enhanced stability and cell-targeted biological efficacy.

Kinetically assembled nanoparticles are fabricated from an advanced class of bioactive macromolecules that have potential utility in counteracting atherosclerotic plaque development via receptor-level blockage of inflammatory cells. In contrast to micellar analogs that exhibit poor potency and structural integrity under physiologic conditions, these kinetic nanoparticle assemblies maintain structural stability and demonstrate superior bioactivity in mediating oxidized low-density lipoprotein (oxLDL) uptake in inflammatory cells.

Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation.

Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors.