title: Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity.
abstract: PPARγ nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPARγ agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200nm PLGA/PVA nanospheres were formulated for the systemic delivery of RSG specifically to macrophages. RSG was encapsulated with over 50% efficiency in the hydrophobic PLGA core and released specifically within the acidifying macrophage phagosomes. In bone marrow derived macrophages, RSG-loaded nanoparticles (RSG-NPs) induce a dose dependent upregulation (1.5 to 2.5-fold) of known PPARγ target genes, with maximal induction at 5μM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10μM. In Ldlr(-/-) mice fed high fat diet, treatment with RSG-NPs alleviated inflammation in white adipose tissue and liver but, unlike treatment with free RSG, did not alter genes associated with lipid metabolism or cardiac function, indicating a reduction in the RSG side effect profile. These biocompatible, biodegradable RSG-NPs represent a preliminary step towards the specific delivery of nuclear receptor agonists for the treatment of macrophage-mediated inflammatory conditions associated with obesity, atherosclerosis and other chronic disease states.
authors.affiliation: Department of Translational Imaging and Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Ave, Houston 77030, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Di Mascolo
authors.forename: Christopher
authors.initials: C
authors.lastname: J Lyon
authors.forename: Santosh
authors.initials: S
authors.lastname: Aryal
authors.forename: Maricela R
authors.initials: MR
authors.lastname: Ramirez
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Patrizio
authors.initials: P
authors.lastname: Candeloro
authors.forename: Michele
authors.initials: M
authors.lastname: Guindani
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: Paolo
authors.initials: P
authors.lastname: Decuzzi
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D054118:Nanospheres / Q000008:administration & dosage* / Q000737:chemistry; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D011142:Polyvinyl Alcohol / Q000737:chemistry; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D011973:Receptors, LDL; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011142:Polyvinyl Alcohol
keywords: Inflammatory diseases; Macrophage targeting; PLGA/PVA nanospheres; PPARγ agonists