Oxygen And Indocyanine Green Loaded Phase-transition Nanoparticle-mediated Photo-sonodynamic Cytotoxic Effects On Rheumatoid Arthritis Fibroblast-like Synoviocytes

Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease of uncertain cause.Abnormal synovium proliferation,proinflammatory cell infiltration,local hypoxia,and angiogenesis jointly promote the progression of RA.Despite the significant progress in the management of RA in the last decades,some patients do not respond well to the therapeutics presently available,or suffer from relapse after initial response,which contribute to further damage of vital joint structures.Photodynamic therapy(PDT)and sonodynamic therapy(SDT)have been proposed and intensively studied due to their minimal invasiveness and improved site selective action.And it is currently believed that the combination of PDT and SDT(i.e.PSDT)may reduce the side effects,while enhancing the curative effect dramatically.Based on the good oxygen carrying capacity2 of liquid perfluorocarbon compounds(PFCs)and the photosensitizer and sonosensitizer properties of indocyanine green(ICG),we aim to develop a novel nanoscale poly(dl-lactide-co-glycolic acid [PLGA])drug delivery system which encapsulates oxygen saturated PFC and ICG(OI-NPs)in this study,and to investigate the cytotoxic effects of OI-NPs mediated PSDT against fibroblast-like synoviocytes(FLSs)and the potential mechanisms involved in vitro.We found that:(1)ICG mediated SDT could induce serious cytotoxicity effect on RA FLSs in vitro.(2)the nanoparticles encapsulating perfluoro-n-pentane(PFP)have a good stability,and the required laser irritation energy is relatively low.(3)multifunctional OI-NPs was a stable and efficient carrier to deliver oxygen and ICG,and enhanced cellular uptake was observed in MH7 A cells with OI-NPs.OI-NPs mediated PSDT caused more serious cell damage and more evident cell apoptosis,compared with other groups,and increased generation of intracellular ROS was detected in MH7 A cells treated with PSDT.In summary,multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green,and OI-NP–mediated PSDT would be a potential cytotoxic treatment for MH7 A cells.This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future.