摘要
Invasive fibroblast-like synoviocytes(FLS),inflammatory macrophages and osteoclasts are the main three contributors to rheumatoid arthritis(RA)progression by promoting synovial inflammation and destructing cartilage and bone.Targeting these three cell types for restoring the inflammatory homeostasis microenvironment may be a promising anti-RA strategy.Herein,we prepared a reactive oxygen species(ROS)-responsive micelles(DPTM)to co-load dexamethasone(DEX)and pristimerin(PRI)for RA therapy.This ROS-responsive system exhibits the following advantages:(1)It makes use of the“ELVIS”effect for passive delivery and targeting the ROS environment of RA-related cells to rapidly release the payload drugs DEX and PRI.(2)Compared with free drugs,DPTM showed stronger effect on the inhibition of RA-FLS proliferation and the promotion of RA-FLS apoptosis.Moreover,DPTM could significantly weaken the migration ability of RA-FLS as indicated by the results of wound healing assay and transwell assay.(3)DPTM exerted stronger cellular uptake and anti-inflammatory effect in M1 macrophages.(4)In the model studying receptor activator of nuclear factor kappa-B ligand(RANKL)-induced differentiation of bone marrow-derived macrophages(BMDMs)to osteoclasts,DPTM showed a stronger inhibitory activity on osteoclast formation as compared to free drugs.Taken together,these results highlighted the potential of DPTM for targeted RA therapy via inhibition of RA-FLS abnormal activation,macrophage polarization and osteoclastogenesis.
基金
supported by the National Natural Science Foundation of China(No.82204724)
the Science and Technology Development Fund,Macao SAR(Nos.0029/2023/AFJ,005/2023/SKL)
the Multi-Year Research Grant(MYRG)of University of Macao(Nos.MYRG2022-00203-ICMS,MYRG-GRG2023-00134-ICMS-UMDF)
Macao Young Scholars Program(No.AM2022019)。
