Combination of NF-kB targeted siRNA and methotrexate in a hybrid nanocarrier towards the effective treatment in rheumatoid arthritis

Weifeng Duan,Huan Li

doi:10.1186/s12951-018-0382-x

Abstract

BackgroundThe transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). Effective treatment of RA is hindered due to the lack of specificity of small molecules in the inflamed joints. In this study, we aimed to develop a unique hybrid-nanoparticles system comprised of calcium phosphate/liposome to deliver NF-kB-targeted siRNA and methotrexate (MTX) to diseased site.ResultsWe have successfully demonstrated that the combination of siRNA and MTX in a calcium phosphate/liposome-based hybrid nanocarrier could effectively treat the RA. We have showed that folate receptor-targeted nanocarrier system significantly suppression the arthritis progression in mice model. Substantial accumulation of F-siRML was observed in LPS-activated macrophages. These kind of activated macrophages are generally present in the RA and osteoarthritis and folate-targeted nanoparticle enables the effective accumulation of therapeutics in the diseased site. The combinational nanoparticles effectively blocked the NF-kB signaling pathways and reduced the expression of pro-inflammatory cytokines. Furthermore, siRML and F-siRML did not show any decrease in the lymphocyte count indicating that it can avoid the adverse effect of MTX.ConclusionTherefore, siRML and F-siRML provides unique benefits of excellent therapeutic efficacy with excellent safety profile in the arthritic mice and could be an promising approach in the treatment of rheumatoid arthritis.

Highlights

The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA)
We expected that small-interfering RNA (siRNA) could potentially downregulate the p65 and thereby M1 macrophages re-polarize into M2 macrophages which are involved in tissue repair
We expected that siRNA could potentially downregulate the p65 and thereby M1 macrophages re-polarize into M2 macrophages which are involved in tissue repair [13]

Summary

Introduction

The transcription factor NF-kB plays an important role in the pathogenesis of rheumatoid arthritis (RA). In RA, immune cells and activated macrophages infiltrate in the synovial tissue and destroy the cartilage and activate the inflammatory signaling pathways [2]. This process results in progressive destruction of bone and cartilage and cause immense pain and disability and there it is called autoimmune disorder [3]. In RA, the inflammatory signals from TNF-α and IL-1β degrades the inhibitory kB protein and thereby NF-kB gets liberated and transfer to the nucleus where they activate several inflammatory signals [8]

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Results

Conclusion