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macrophage-mimetic liposome adsorbing endotoxins for sepsis treatment

Macrophage-mimetic liposome adsorbing endotoxins for sepsis ...

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2018年第十二届中国药物制剂大会

作者：姜礼贤 Ruixiang Li Jian’ge Zhang Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine

OBJECTIVE. Sepsis is a systemic inflammatory response syndrome mainly caused by bacterial infections. Severe sepsis may induce damage to organs and subsequent septic shock, which has become the leading cause of death in ICU patients worldwide. The common treatment for bacterial infections and sepsis is far from satisfaction. To develop a novel therapy for sepsis is urgently needed. Endotoxins, also refers to lipopolysaccharide（LPS）, have been regarded as the most important pathogenic factor in Gram-negative bacterial sepsis. Inspired by the intrinsic LPS-binding capacity of macrophage, a macrophage-mimetic liposome（M-Lipo） was developed for LPS neutralization. METHODS. The macrophage-mimetic liposome was designed under a hybrid concept. Firstly, macrophage-derived micro vesicles（MMV） were isolated from RAW264.7 cells by chemical stimulation, serving as membrane source. Then, the natural MMV was fused with artificial liposome by an extrusion method to prepare hybrid M-Lipo. Representative proteins of M-Lipo were detected using SDS-PAGE and Western blotting. The in vivo circulation of PEGylated M-Lipo was measured. The neutralization of LPS by M-Lipo was determined. And the therapeutic effect of M-Lipo was observed in LPS-infected cells. Finally, the survivals of sepsis-bearing mice after M-Lipo injection were observed. RESULTS. The result showed the M-Lipo had similar surface protein of macrophages, indicating MLipo could specifically bind LPS just like macrophages. As the pharmacokinetics experiment presented, MLipo showed 16% retention in blood and 382% more than the natural MMV at 12 h, indicating the combination of natural MMV and artificial lipid could integrate their advantages, which presumably could promote the elimination of LPS in vivo. The in vitro neutralization assay showed a neutralization capacity of 50 ng LPS per mg of M-Lipo. And M-Lipo significantly reduced LPS-induced inflammatory factor levels and i NOs levels. In a mouse LPS sensitive model, trea

关键词： macrophage-mimetic liposome hybrid LPS sepsis

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