Co-delivery of Interferon Regulatory Factor 5 (IRF5) siRNA and dasatinib by a disulfide bond bearing polymeric carrier for enhanced anti-inflammatory effects

Abstract

Co-delivery of chemical drugs and nucleic acids has attracted a great interest recently for treatment of inflammatory diseases. Dasatinib (DB), a tyrosine kinase inhibitor with anti-cancer effects, and Interferon Regulatory Factor 5 (IRF5) siRNA have shown anti-inflammatory effects. In the present study, a novel redox-responsive polymeric micelle was designed for co-delivery of DB and IRF5 siRNA-expressing plasmid (psiRF5) to enhance anti-inflammatory effects on macrophages. psiRF5 was condensed efficiently to redox-responsive micelles of DBconjugated chitosan (CN) composed of disulfide bond, from different molecular weights of CN to form CN-SS-DB/ psiRF5 micelles. The micelles with optimum N/P ratios had particle sizes of 287.8 and 245.4 nm and positive zeta potentials. The disulfide bond bearing micelles showed a redox-responsive drug release, protected the plasmid from being dissociated or degraded in exposure with heparin, serum and DNase I, and significantly enhanced the transfection efficiency and IRF5-gene silencing compared to naked psiRF5. The optimum micelles exhibited a dramatic reduction in IRF5 expression and revealed a notably higher anti-inflammatory effect than either DB or psiRF5, as indicated by more IL-10 and less IL-6 and TNF-alpha production by LPS-stimulated RAW264.7 macrophages incubated with the co-delivery system. The resultant nanocarriers might be promising for more effective treatment of inflammatory diseases.