Co-delivery of Andrographolide and Notch1-targeted siRNA to Macrophages with Polymer-based Nanocarrier for Enhanced Anti-inflammation

Abstract

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 Notch1 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 Notch1 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-κB (NF-κB) signal activation, but also interfered the Notch1 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 Notch1 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.