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Co-Delivery of Interferon Regulatory Factor 5 (Irf5) Sirna and Dasatinib by a Disulfide Bond Bearing Polymeric Carrier for Enhanced Anti-Inflammatory Effects Publisher Pubmed



Vakilzadeh H1 ; Varshosaz J1 ; Dinari M2 ; Mirian M3 ; Soghrati S1
Authors
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Authors Affiliations
  1. 1. Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Chemistry, Isfahan University of Technology, Isfahan, Iran
  3. 3. Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, Iran

Source: International Journal of Biological Macromolecules Published:2024


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 DB-conjugated 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-α 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. © 2024
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