Advanced Healthcare Materials 2014-09-01

Development of therapeutic polymeric nanoparticles for the resolution of inflammation.

Suresh Gadde, Orli Even-Or, Nazila Kamaly, Apoorva Hasija, Philippe G Gagnon, Krishna H Adusumilli, Andrea Erakovic, Anoop K Pal, Xue-Qing Zhang, Nagesh Kolishetti, Jinjun Shi, Edward A Fisher, Omid C Farokhzad

文献索引：Adv. Healthc. Mater. 3(9) , 1448-56, (2014)

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摘要

Liver X receptors (LXRs) attenuate inflammation by modulating the expression of key inflammatory genes, making LXRs and their ligands particularly attractive candidates for therapeutic intervention in cardiovascular, metabolic, and/or inflammatory diseases. Herein, enhanced proresolving activity of polymeric nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (LXR-NPs) is demonstrated, developed from a combinatorial library of more than 70 formulations with variations in critical physicochemical parameters. In vitro studies on peritoneal macrophages confirm that LXR-NPs are significantly more effective than the free agonist at downregulating pro-inflammatory mediators (MCP-1 and TNFα), as well as inducing the expression of LXR target genes (ABCA1 and SREBP1c). Through a zymosan-induced acute peritonitis in vivo model, LXR-NPs are found to be more efficient than free GW3965 at limiting the recruitment of polymononuclear neutrophils (50% vs 17%), suppressing the gene expression and secretion of pro-inflammatory factors MCP-1 and TNFα in peritoneal macrophages, and decreasing the resolution interval up to 4 h. Furthermore, LXR-NPs suppress the secretion of MCP-1 and TNFα by monocytes and macrophages more efficiently than the commercial drug dexamethasone. Overall, these findings demonstrate that LXR-NPs are capable of promoting resolution of inflammation and highlight the prospect of LXR-based nanotherapeutics for inflammatory diseases. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.