Delivery of Ferulic Acid with PEGylated Diphenylalanine Nanoparticles for Pre-arthritis Therapy
Abstract Background: In the therapy of rheumatoid arthritis (RA), treatment starting at the late stage of disease is probably associated with a worse disease outcome. Thus, blocking the RA developments at the early stage of inflammation with efficacious and safe agents might present a promising strategy. Ferulic acid (FA), a safe and active component extracted from Chinese medicine, shows excellent anti-inflammatory properties in various inflammatory diseases. However, the application of FA as an anti-inflammatory drug is hindered by its instability and short half-life in vivo. The aim of this study is to design a feasible drug delivery system to improve the therapeutic efficacy of FA in the treatment of RA and investigate whether treatment initiated at early stage of arthritis would effectively prevent the development of arthritis.Method: A diphenylalanine-based nanoparticle was constructed by the self-stacking of NH2-Phe-Phe-COOH and poly (ethylene glycol) methyl ether amine (PEG5k-NH2) using the glutaraldehyde (GTA) as a cross-linker. The therapeutic outcomes of treatment using FA-loaded PEGylated Phe-Phe nanoparticles were explored at both pre-arthritis stage and fully-developed arthritis stage. Results: We find that the FA-loaded PEGylated Phe-Phe nanoparticles are biocompatible and could effectively inhibit the production of reactive oxygen species in inflammatory condition. After being intravenously administrated in vivo, the FA-loaded PEGylated Phe-Phe nanoparticles show prolonged circulation time and enhanced accumulation in arthritic joints. More importantly, the pre-arthritis treatment with the FA-loaded PEGylated Phe-Phe nanoparticles can significantly block the progression of RA compared with treatment started at the late stage of arthritis.Conclusions: Our results demonstrated FA-loaded PEGylated Phe-Phe nanoparticles could greatly improve the therapeutic efficacy of FA and ultimately prevent the progression of arthritis in a low activity when applied in pre-arthritis phase. This therapeutic outcome confirmed the treatment initiated in very early disease phases is effective to prevent arthritis progression to full-blown disease.