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

Journal of controlled release : official journal of the Controlled Release Society (2013-06-25)
Daniele Di Mascolo, Christopher J Lyon, Santosh Aryal, Maricela R Ramirez, Jun Wang, Patrizio Candeloro, Michele Guindani, Willa A Hsueh, Paolo Decuzzi
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Poly(vinyl alcohol), Mw 89,000-98,000, 99+% hydrolyzed
Sigma-Aldrich
Poly(vinyl alcohol), Mw 9,000-10,000, 80% hydrolyzed
Sigma-Aldrich
Poly(vinyl alcohol), 87-90% hydrolyzed, average mol wt 30,000-70,000
Sigma-Aldrich
Mowiol® 4-88, Mw ~31,000
Sigma-Aldrich
Poly(vinyl alcohol), Mw 13,000-23,000, 87-89% hydrolyzed
Sigma-Aldrich
Poly(vinyl alcohol), Mw 146,000-186,000, 99+% hydrolyzed
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Rosiglitazone, ≥98% (HPLC)
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Poly(vinyl alcohol), Mw 85,000-124,000, 99+% hydrolyzed
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Poly(vinyl alcohol), Mw 31,000-50,000, 98-99% hydrolyzed
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Mowiol® 18-88, Mw ~130,000
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Poly(vinyl alcohol), average Mw 85,000-124,000, 87-89% hydrolyzed
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Poly(vinyl alcohol), average Mw 31,000-50,000, 87-89% hydrolyzed
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Poly(vinyl alcohol), Fully hydrolyzed
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Poly(vinyl alcohol), average Mw 13,000-23,000, 98% hydrolyzed
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Mowiol® 10-98, Mw ~61,000
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Poly(vinyl alcohol), average Mw 146,000-186,000, 87-89% hydrolyzed
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Mowiol® 8-88, Mw ~67,000
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Mowiol® 40-88, average Mw ~205,000 g/mol
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Poly(vinyl alcohol), average Mw 130,000, 99+% hydrolyzed
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Mowiol® 4-98, Mw ~27,000
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Mowiol® 28-99, Mw ~145,000
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Mowiol® 20-98, Mw ~125,000
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Mowiol® 56-98, Mw ~195,000
Sigma-Aldrich
Mowiol® 6-98, Mw ~47,000