Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

Abstract

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...

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Atherosclerosis by Affecting Foam Cell Formation and Efferocytosis

“…Our results revealed that MR blockade in macrophages was sufficient to mitigate atherosclerosis and likely improve plaque vulnerability, indicating that macrophage MR plays essential roles in the process of atherogenesis. It is plausible to treat atherosclerosis by selectively blockade of MR in macrophages using nanoparticles, which have been proved to be effective as delivery vehicles in the setting of atherosclerosis (3,(23)(24)(25)(26). This strategy allows local delivery of agents to block macrophage MR in atherosclerotic lesions, likely improving efficacy and circumventing systemic side effects.…”

Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

“…Additionally, the AMs possess the benefit of a tunable structure, in which the end group can be modified to promote self-assembly to cardiovascular stents, catheter balloons or other devices, allowing for a wide range of functional coatings. Localization to arterial plaques could also occur due to the targeting capability of AM nanoassemblies, which could be further enhanced by infusion catheter delivery [35]. …”

A Broad‐Spectrum ROS‐Eliminating Material for Prevention of Inflammation and Drug‐Induced Organ Toxicity

“…Also, synthetic dendritic polyglycerol sulfates were able to dampen leukocyte extravasation in a dermatitis mouse model 42. Nanoparticles assembled by sugar‐based amphiphilic polymers were effective to counteract atherosclerosis, a chronic inflammatory disease 43. These studies have unambiguously demonstrated the effectiveness of anti‐inflammatory material‐derived nanotherapies.…”