Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis

Xue Qing Zhang, Orli Even-Or, Xiaoyang Xu, Mariska van Rosmalen, Lucas Lim, Suresh Gadde, Omid C. Farokhzad, Edward A. Fisher

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr -/- mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. The nuclear hormone receptor LXR has a number of properties that would be valuable in preventing or treating atherosclerosis, the underlying cause of heart attacks and stroke. Nanoparticles containing an activator of LXR are described and demonstrated to produce significant atherosclerosis benefits without stimulating liver lipid metabolism in a mouse model of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)228-236
Number of pages9
JournalAdvanced Healthcare Materials
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

Keywords

  • Atherosclerosis
  • Drug delivery
  • Liver X receptor (LXR)
  • Nanoparticles

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