Chronic inflammatory responses induced by macrophages play a pivotal role in the progression of atherosclerosis. In the present study, a multifunctional nanocarrier based on poly（ethylene glycol）-block-poly（L-aspar...Chronic inflammatory responses induced by macrophages play a pivotal role in the progression of atherosclerosis. In the present study, a multifunctional nanocarrier based on poly（ethylene glycol）-block-poly（L-aspartic acid） grafted with diethylenetriamine, lysine and cholic acid （PEG-PAsp（DETA）-Lys-CA2） polymer was synthesized for co-delivery of andrographolide and siRNA targeting Notchl gene to alleviate the inflammatory response in macrophages. The nanocarrier exerted low cytotoxicity as well as high performance in drug/siRNA co-delivery. In vitro studies demonstrated the co-delivery of andrographolide and Notchl siRNA not only significantly inhibited lipopolysaccharide （LPS）-activated interleukin-6 （IL-6） and monocytes chemotactic protein 1 （MCP-1） expression as well as blocked nuclear factor-rd3 （NF-rd3） signal activation, but also interfered the Notchl gene expression and increased anti-inflammatory cytokines such as interleukin-10 （IL-10） and arginase-1 expression obviously in macrophages. These results suggested that the combination therapy based on Notchl siRNA and andrographolide co-delivered nanocarrier, i.e. suppressing the expression of proinflammatory cytokines while simultaneously increasing anti-inflammatory factors expression, be a feasible strategy for atherosclerosis treatment.展开更多
基金financially supported by the National Natural Science Foundation of China (No. U1401242)National Basic Research Program of China (No. 2015CB755500)+1 种基金the Guangdong Innovative and Entrepreneurial Research Team Program (No. 2013S086)the Fundamental Research Funds for the Central Universities (Nos. 17lgjc01 and 17lgpy08)
文摘Chronic inflammatory responses induced by macrophages play a pivotal role in the progression of atherosclerosis. In the present study, a multifunctional nanocarrier based on poly（ethylene glycol）-block-poly（L-aspartic acid） grafted with diethylenetriamine, lysine and cholic acid （PEG-PAsp（DETA）-Lys-CA2） polymer was synthesized for co-delivery of andrographolide and siRNA targeting Notchl gene to alleviate the inflammatory response in macrophages. The nanocarrier exerted low cytotoxicity as well as high performance in drug/siRNA co-delivery. In vitro studies demonstrated the co-delivery of andrographolide and Notchl siRNA not only significantly inhibited lipopolysaccharide （LPS）-activated interleukin-6 （IL-6） and monocytes chemotactic protein 1 （MCP-1） expression as well as blocked nuclear factor-rd3 （NF-rd3） signal activation, but also interfered the Notchl gene expression and increased anti-inflammatory cytokines such as interleukin-10 （IL-10） and arginase-1 expression obviously in macrophages. These results suggested that the combination therapy based on Notchl siRNA and andrographolide co-delivered nanocarrier, i.e. suppressing the expression of proinflammatory cytokines while simultaneously increasing anti-inflammatory factors expression, be a feasible strategy for atherosclerosis treatment.
