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

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalAdvanced Healthcare Materials
Volume3
Issue number9
Pages (from-to)1448–1456
ISSN2192-2640
Publication statusPublished - 2014
Externally publishedYes

Cite this

Gadde, S., Even-Or, O., Kamaly, N., Hasija, A., Gagnon, P. G., Adusumilli, K. H., Erakovic, A., Pal, A. K., Zhang, X-Q., Kolishetti, N., Shi, J., & Fisher, E. A. (2014). Development of Therapeutic Polymeric Nanoparticles for the Resolution of Inflammation. Advanced Healthcare Materials, 3(9), 1448–1456.