open access publication

Article, 2022

Nanoconfined anti-oxidizing RAFT nitroxide radical polymer for reduction of low-density lipoprotein oxidation and foam cell formation

Nanoscale Advances, ISSN 2516-0230, Volume 4, 3, Pages 742-753, 10.1039/d1na00631b

Contributors

Basak, Suman 0000-0002-9519-9117 [1] Khare, Harshvardhan Ajay 0000-0001-5933-2075 [1] [2] Kempen, Paul Joseph 0000-0003-2179-2257 [1] Kamaly, Nazila 0000-0002-9716-5121 [3] Almdal, Kristoffer 0000-0002-5490-9303 (Corresponding author) [1]

Affiliations

  1. [1] Technical University of Denmark
    2. [NORA names: DTU Technical University of Denmark; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] University of Copenhagen
    3. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  3. [3] Imperial College London
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD]

Abstract

Atherosclerosis is a leading cause of death worldwide. Antioxidant therapy has been considered a promising treatment modality for atherosclerosis, since reactive oxygen species (ROS) play a major role in the pathogenesis of atherosclerosis. We developed ROS-scavenging antioxidant nanoparticles (NPs) that can serve as an effective therapy for atherosclerosis. The newly developed novel antioxidant ROS-eliminating NPs were synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization and act as a superoxide dismutase (SOD) mimetic agent. SOD is an anti-ROS enzyme which is difficult to use for passive delivery due to its low half-life and stability. Copolymers were synthesized using different feed ratios of 2,2,6,6-tetramethyl-4-piperidyl methacrylate (PMA) and glycidyl methacrylate (GMA) monomers and an anti-ROS nitroxyl radical polymer was prepared via oxidation. The copolymer was further conjugated with a 6-aminofluorescein via a oxirane ring opening reaction for intracellular delivery in RAW 264.7 cells. The synthesized copolymers were blended to create NPs (∼150 nm size) in aqueous medium and highly stable up to three weeks. The NPs were shown to be taken up by macrophages and to be cytocompatible even at high dose levels (500 μg mL-1). Finally, the nitroxide NPs has been shown to inhibit foam cell formation in macrophages by decreasing internalization of oxidized low-density lipoproteins.

Keywords

PMA, RAW, RAW 264.7 cells, addition-fragmentation chain-transfer, agents, antioxidant nanoparticles, antioxidant therapy, aqueous media, atherosclerosis, cell formation, cells, chain-transfer, copolymers, death, decreased internalization, delivery, dismutase, dose levels, effective therapy, enzyme, feed ratio, feeding, foam, foam cell formation, formation, glycidyl methacrylate, half-life, highest dose level, inhibited foam cell formation, internalization of oxidized low-density lipoprotein, intracellular delivery, levels, lipoprotein, lipoprotein oxidation, low half-life, low-density lipoprotein, low-density lipoprotein oxidation, macrophages, medium, methacrylate, mimetic agent, modalities, monomer, nanoparticles, nitroxide, nitroxide radical polymers, nitroxyl radical polymers, opening reaction, oxidation, oxirane, oxirane ring opening reaction, oxygen species, passive delivery, pathogenesis, pathogenesis of atherosclerosis, polymer, polymerization, radical polymers, ratio, reaction, reactive oxygen species, reduction, reversible addition-fragmentation chain-transfer, ring-opening reaction, species, stability, superoxide, superoxide dismutase, synthesized copolymers, therapy, treatment, treatment modalities, weeks

Funders

  • Department of Health and Social Care
  • Danish Agency for Science and Higher Education
  • Lundbeck Foundation

Data Provider: Digital Science

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