4-Iodo-6-phenylpyrimidine (4-IPP) suppresses fibroblast-like synoviocyte- mediated inflammation and joint destruction associated with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease that significantly impacts patients' quality of life. Fibroblast-like synovial cells (FLSs) within the synovial intima exhibit "tumor-like" properties such as increased proliferation, migration, and invasion. Activation of FLSs and secretion of pro-inflammation factors result in pannus formation and cartilage destruction. As an inhibitor of the cytokine, macrophage migration inhibitory factor (MIF), 4-Iodo-6-phenylpyrimidine (4-IPP) has been shown to reduce cell proliferation, migration, invasion, and the secretion of pro-inflammatory mediators in a variety of diseases. However, the usefulness of 4-IPP for RA treatment has not been assessed and was the purpose of this study. In vitro, 4-IPP was demonstrated to inhibit proliferation, migration, and invasion of RA FLSs, as well as the expression of pro-inflammatory cytokines. 4-IPP was also shown to inhibit MIF-induced phosphorylation of ERK, JNK, and p38, as well as reduce expression of COX2 and PGE2. In order to efficiently deliver 4-IPP to anatomical RA sites, we developed lactic-co-glycolic acid (PLGA) nanospheres, which not only protected 4-IPP from degradation but also controlled the release of 4-IPP. 4-IPP/PLGA nanospheres had potent anti-inflammatory activity and a high degree of biosafety. Results showed that local 4-IPP concentration was increased by nanosphere delivery, effectively reducing the inflammatory microenvironment as well as synovial inflammation, joint swelling, and cartilage destruction in a collagen-induced rheumatoid arthritis (CIA) rat model. Therefore, 4-IPP nanospheres are a sustained-release delivery system that may be an effective therapeutic strategy for RA treatment.