title: Nanotherapeutics for inhibition of atherogenesis and modulation of inflammation in atherosclerotic plaques.
abstract: OBJECTIVE
  Atherosclerotic development is exacerbated by two coupled pathophysiological phenomena in plaque-resident cells: modified lipid trafficking and inflammation. To address this therapeutic challenge, we designed and investigated the efficacy in vitro and ex vivo of a novel 'composite' nanotherapeutic formulation with dual activity, wherein the nanoparticle core comprises the antioxidant α-tocopherol and the shell is based on sugar-derived amphiphilic polymers that exhibit scavenger receptor binding and counteract atherogenesis.
  
  
  RESULTS
  Amphiphilic macromolecules were kinetically fabricated into serum-stable nanoparticles (NPs) using a core/shell configuration. The core of the NPs comprised either of a hydrophobe derived from mucic acid, M12, or the antioxidant α-tocopherol (α-T), while an amphiphile based on PEG-terminated M12 served as the shell. These composite NPs were then tested and validated for inhibition of oxidized lipid accumulation and inflammatory signalling in cultures of primary human macrophages, smooth muscle cells, and endothelial cells. Next, the NPs were evaluated for their athero-inflammatory effects in a novel ex vivo carotid plaque model and showed similar effects within human tissue. Incorporation of α-T into the hydrophobic core of the NPs caused a pronounced reduction in the inflammatory response, while maintaining high levels of anti-atherogenic efficacy.
  
  
  CONCLUSIONS
  Sugar-based amphiphilic macromolecules can be complexed with α-T to establish new anti-athero-inflammatory nanotherapeutics. These dual efficacy NPs effectively inhibited key features of atherosclerosis (modified lipid uptake and the formation of foam cells) while demonstrating reduction in inflammatory markers based on a disease-mimetic model of human atherosclerotic plaques.
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Lewis
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Latrisha K
authors.initials: LK
authors.lastname: Petersen
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: York
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Sonali
authors.initials: S
authors.lastname: Ahuja
authors.affiliation: Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA.
authors.forename: Hoonbyung
authors.initials: H
authors.lastname: Chae
authors.affiliation: Department of Pharmacology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Joseph
authors.affiliation: Division of Vascular Surgery, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
authors.forename: Saum
authors.initials: S
authors.lastname: Rahimi
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Uhrich
authors.affiliation: Division of Vascular Surgery, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Haser
authors.affiliation: Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA moghe@rutgers.edu.
authors.forename: Prabhas V
authors.initials: PV
authors.lastname: Moghe
mesh_terms: D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL
keywords: Alpha-tocopherol; Atherosclerosis; Inflammation; Macrophages; Nanotechnology