Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity

• DOI: 10.1016/j.jconrel.2013.06.012
• Publication Date: 2013-06-18T19:50:38Z
• Authors: Daniele Di Mascolo; Christopher J. Lyon; Santosh Aryal; Maricela R. Ramirez; Jun Wang; Patrizio Candeloro; Michele Guindani; Willa A. Hsueh; Paolo Decuzzi
• Keywords: Male; Adipose Tissue, White; Anti-Inflammatory Agents; Bone Marrow Cells; Cell Line; Hepatitis; Mice; 03 medical and health sciences; Animals; Hypoglycemic Agents; Obesity; Cells, Cultured; Inflammation; Mice, Knockout; 2. Zero hunger; 0303 health sciences; Macrophages; Myocardium; 3. Good health; Inflammatory diseases; Macrophage targeting; PLGA/PVA nanospheres; PPARγagonists; Mice, Inbred C57BL; Gene Expression Regulation; Receptors, LDL; Polyvinyl Alcohol; Nanospheres

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.