Polyethylene Glycol-grafted Poly Alpha-lipoic Acid-dexamethasone Nanoparticles For Osteoarthritis

Objective:The objective of this thesis is to investigate the application of polyethylene glycol-grafted poly alpha-lipoic acid-dexamethasone nanoparticles(NP_DXM/PPLA)in the treatment of osteoarthritis（OA）,and to elucidate the mechanism of action of NP_DXM/PPLAXM/PPLA on osteoarthritis in mice.It would provide an experimental basis for exploring the therapeutic of osteoarthritis with dexamethasone carried by polymer nanoparticles.Methods:Polyethylene glycol-grafted poly alpha-lipoic acid-dexamethasone nanoparticles(NP_DXM/PPLA)were synthesized by polymerization and hydrophobic interactions,and their particle size,stability,and release of dexamethasone were measured.Mouse osteoarthritis models were established by injecting iodoacetic into the mouse joint cavity.Three days later,they were randomly divided into four groups and treated with saline,free dexamethasone（DXM）,Polyethylene glycol-grafted poly alpha-lipoic nanoparticles(NP_PPLA),and NP_DXM/PPLAXM/PPLA through the joint cavity.The effects of NP_DXM/PPLAXM/PPLA on osteoarthritis in mice were evaluated by imaging reconstruction and immunohistopathology.Flow cytometry（FCM）and Confocal laser scanning microscope（CLSM）were used to observe the anti-inflammatory and anti-oxidative mechanism of NP_DXM/PPLAXM/PPLA in macrophages.Results:The average particle size of NP_DXM/PPLAXM/PPLA nanoparticles was（24.0+1.2）nm.The morphology and structure of the nanoparticles were stable in a PBS solution at pH=7.4.The anti-inflammatory results show that:compared with the free DXM group,NP_DXM/PPLAXM/PPLA nanoparticles have more obvious anti-inflammatory and antioxidant effects on macrophages;H&E staining showed that chondrocyte destruction,synovial tissue proliferation and inflammatory cell infiltration were seen in all four groups.However,compared to other groups,the NP_DXM/PPLAXM/PPLA group Cartilage destruction was slight,synovial hyperplasia was not obvious,and inflammatory cells were less infiltrated,closer to normal knee joint structure;The comparison of bone volume fraction（BV/TV）in the subchondral region of the knee joint of mice with micro computed tomography（Micro CT）found that the bone mass in the saline treatment group was about 55%,while the bone mass in the NP_DXM/PPLAXM/PPLA treatment group was90%,The bone mass of the knee subchondral bone in the saline group was significantly reduced.The NP_DXM/PPLAXM/PPLA treatment group is closer to bone in healthy mice.Conclusion:1.NP_DXM/PPLAXM/PPLA nanoparticles could be released in macrophages and inhibit their inflammatory response;2.NP_DXM/PPLAXM/PPLA nanoparticles could alleviate the symptoms of osteoarthritis,reduce cartilage damage,synovial hyperplasia,and inflammatory cell infiltration.