Daniel R Lewis1, Latrisha K Petersen2, Adam W York2, Sonali Ahuja2, Hoonbyung Chae2, Laurie B Joseph3, Saum Rahimi4, Kathryn E Uhrich5, Paul B Haser4, Prabhas V Moghe6. 1. Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, USA Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA. 2. Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854, USA. 3. Department of Pharmacology, Rutgers University, Piscataway, NJ, USA. 4. Division of Vascular Surgery, Robert Wood Johnson Medical School, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA. 5. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ, USA. 6. 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.
Abstract
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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