title: Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.
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.
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Xue-Qing
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Orli
authors.initials: O
authors.lastname: Even-Or
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Xu
authors.forename: Mariska
authors.initials: M
authors.lastname: van Rosmalen
authors.forename: Lucas
authors.initials: L
authors.lastname: Lim
authors.forename: Suresh
authors.initials: S
authors.lastname: Gadde
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors
keywords: atherosclerosis; drug delivery; liver X receptor (LXR); nanoparticles