Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity
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- 作者：Daniele Di Mascolo ; Christopher J. Lyon ; Santosh Aryal ; Maricela R. Ramirez ; Jun Wang ; Patrizio C ; eloro ; Michele Guindani ; Willa A. Hsueh ; Paolo Decuzzi
- 关键词：PPAR¦Ã agonists ; Macrophage targeting ; PLGA/PVA nanospheres ; Inflammatory diseases
- 刊名：Journal of Controlled Release
- 出版年：2013
- 出版时间：28 September, 2013
- 年：2013
- 卷：170
- 期：3
- 页码：460-468
- 全文大小：1343 K
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.