文摘
PPAR¦Ã nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPAR¦Ã agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200 nm 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 PPAR¦Ã target genes, with maximal induction at 5 ¦ÌM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10 ¦ÌM. 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.