title: Development of therapeutic polymeric nanoparticles for the resolution of inflammation.
abstract: Liver X receptors (LXRs) attenuate inflammation by modulating the expression of key inflammatory genes, making LXRs and their ligands particularly attractive candidates for therapeutic intervention in cardiovascular, metabolic, and/or inflammatory diseases. Herein, enhanced proresolving activity of polymeric nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (LXR-NPs) is demonstrated, developed from a combinatorial library of more than 70 formulations with variations in critical physicochemical parameters. In vitro studies on peritoneal macrophages confirm that LXR-NPs are significantly more effective than the free agonist at downregulating pro-inflammatory mediators (MCP-1 and TNFα), as well as inducing the expression of LXR target genes (ABCA1 and SREBP1c). Through a zymosan-induced acute peritonitis in vivo model, LXR-NPs are found to be more efficient than free GW3965 at limiting the recruitment of polymononuclear neutrophils (50% vs 17%), suppressing the gene expression and secretion of pro-inflammatory factors MCP-1 and TNFα in peritoneal macrophages, and decreasing the resolution interval up to 4 h. Furthermore, LXR-NPs suppress the secretion of MCP-1 and TNFα by monocytes and macrophages more efficiently than the commercial drug dexamethasone. Overall, these findings demonstrate that LXR-NPs are capable of promoting resolution of inflammation and highlight the prospect of LXR-based nanotherapeutics for inflammatory diseases.
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Gadde
authors.affiliation: Department of Cell Biology and the Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Orli
authors.initials: O
authors.lastname: Even-Or
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nazila
authors.initials: N
authors.lastname: Kamaly
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Hasija
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Gagnon
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Krishna H
authors.initials: KH
authors.lastname: Adusumilli
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Erakovic
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anoop K
authors.initials: AK
authors.lastname: Pal
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.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kolishetti
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Cell Biology and the Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY 10016.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D001565:Benzoates / Q000737:chemistry / Q000627:therapeutic use; D001596:Benzylamines / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011108:Polymers
keywords: drug delivery systems; inflammation; liver X receptor agonist; nanomedicine; polymeric nanoparticles