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Antioxidant Response Activating nanoParticles (ARAPas) localize to atherosclerotic plaque and locally activate the

Sophie Maiocchi1,2,3,4, Ana Cartaya3,4,5, Sydney Thai6

  • 1Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, NC 27599, USA. edward_bahnson@med.unc.edu.

Biomaterials Science
|January 25, 2022
PubMed

Insights

Researchers developed novel nanoparticles (ARAPas) that deliver antioxidant drugs directly to atherosclerotic plaques. These nanoparticles target macrophages and dysfunctional endothelium, showing promise for treating cardiovascular disease.

Area of Science:

  • Cardiovascular Research
  • Nanomedicine
  • Redox Biology

Background:

  • Atherosclerosis is a leading cause of death globally, with limited novel therapeutic options.
  • Redox dysfunction significantly drives atherosclerotic progression, but clinical translation of redox-based therapies is challenging.
  • Targeted delivery of redox interventions to specific cellular domains is crucial for effective treatment.

Purpose of the Study:

  • To develop Antioxidant Response Activating nanoParticles (ARAPas) for targeted delivery of redox-based interventions to atherosclerotic plaques.
  • To encapsulate the Nrf2 activator drug, CDDO-Methyl (CDDOMe), within biocompatible polymeric nanoparticles using flash nanoprecipitation (FNP).
  • To evaluate the physicochemical properties, cellular uptake, drug release, anti-inflammatory effects, and plaque accumulation of CDDOMe-ARAPas.

Main Methods:

  • Synthesis of CDDOMe-loaded nanoparticles (CDDOMe-ARAPas) via flash nanoprecipitation (FNP).
  • Characterization of physicochemical properties and *in vitro* internalization by murine macrophages.
  • Assessment of drug release via Nrf2-driven GFP fluorescence and evaluation of anti-inflammatory effects in activated macrophages.
  • *In vivo* studies in ApoE-/- and LDLr-/- mouse models of atherosclerosis to assess plaque accumulation and Nrf2 target gene expression.

Main Results:

  • CDDOMe-ARAPas were successfully synthesized and demonstrated *in vitro* uptake by macrophages.
  • Nrf2-driven GFP fluorescence confirmed CDDOMe release.
  • CDDOMe-ARAPas exhibited anti-inflammatory effects in classically activated macrophages.
  • Selective accumulation of CDDOMe-ARAPas in atherosclerotic plaques of ApoE-/- and LDLr-/- mice was observed.
  • Increased gene expression of Nrf2-transcriptional targets in the atherosclerotic aortic arch was confirmed.

Conclusions:

  • Targeting atherosclerotic plaques effectively enhances the delivery of redox-based interventions.
  • CDDOMe-ARAPas show potential for targeted delivery of Nrf2 activators to inhibit atherosclerotic plaque progression.
  • Further studies are warranted to assess the therapeutic efficacy of intra-plaque Nrf2 activation using CDDOMe-ARAPas.

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