Drug Repositioning of Metformin Encapsulated in PLGA Combined with Photothermal Therapy Ameliorates Rheumatoid Arthritis

Abstract

Purpose: Rheumatoid arthritis (RA) is a highly prevalent form of autoimmune disease that affects nearly 1% of the global population by causing severe cartilage damage and inflammation. Despite its prevalence, previous efforts to prevent the perpetuation of RA have been hampered by therapeutics' cytotoxicity and poor delivery to target cells. The present study exploited drug repositioning and nanotechnology to convert metformin, a widely used antidiabetic agent, into an anti-rheumatoid arthritis drug by designing poly(lacticco-glycolic acid) (PLGA)-based spheres. Moreover, this study also explored the thermal responsiveness of the IL-22 receptor, a key regulator of Th-17, to incorporate photothermal therapy (PTT) into the nanodrug treatment. Materials and Methods: PLGA nanoparticles were synthesized using the solvent evaporation method, and metformin and indocyanine green (ICG) were encapsulated in PLGA in a dropwise manner. The nanodrug's in vitro anti-inflammatory properties were examined in J744 and FLS via real-time PCR. PTT was induced by an 808 nm near-infrared (NIR) laser, and the anti-RA effects of the nanodrug with PTT were evaluated in DBA/1 collagen-induced arthritis (CIA) mice models. Further evaluation of anti-RA properties was carried out using flow cytometry, immunofluorescence analysis, and immunohistochemical analysis. Results: The encapsulation of metformin into PLGA allowed the nanodrug to enter the target cells via macropinocytosis and clathrinmediated endocytosis. Metformin-encapsulated PLGA (PLGA-MET) demonstrated promising anti-inflammatory effects by decreasing the expression of pro-inflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha), increasing the expression of anti-inflammatory cytokines (IL10 and IL-4), and promoting the polarization of M1 to M2 macrophages in J774 cells. The treatment of the nanodrug with PTT exhibited more potent anti-inflammatory effects than free metformin or PLGA-MET in CIA mice models. Conclusion: These results demonstrated that PLGA-encapsulated metformin treatment with PTT can effectively ameliorate inflammation in a spatiotemporal manner.