TY - JOUR
T1 - Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity
AU - Di Mascolo, Daniele
AU - Lyon, Christopher J.
AU - Aryal, Santosh
AU - Ramirez, Maricela R.
AU - Wang, Jun
AU - Candeloro, Patrizio
AU - Guindani, Michele
AU - Hsueh, Willa A.
AU - Decuzzi, Paolo
N1 - Funding Information:
PD acknowledges support from the Methodist Hospital Research Institute for conducting this research activity. DDM acknowledges the support of the EU Commission , the European Social Fund and the Department 11 “Culture-Education-University-Research-Technological Innovation — Higher Education” of Calabria Region (POR Calabria FSE 2007/2013 ).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2013
Y1 - 2013
N2 - 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, 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 PPARγ target genes, with maximal induction at 5 μM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10 μM. 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.
AB - 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, 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 PPARγ target genes, with maximal induction at 5 μM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10 μM. 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.
KW - Inflammatory diseases
KW - Macrophage targeting
KW - PLGA/PVA nanospheres
KW - PPARγagonists
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U2 - 10.1016/j.jconrel.2013.06.012
DO - 10.1016/j.jconrel.2013.06.012
M3 - Article
C2 - 23791978
AN - SCOPUS:84885130620
VL - 170
SP - 460
EP - 468
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 3
ER -