Construction Of Diselenide-based Nanodrugs And Their Applications In Inflamatory Diseases Treatment

The application of stimuli-responsive drug delivery systems in disease therapy is an effective strategy.Inflammatory diseases cover many diseases with signs of abnormal inflammation,mainly caused by the attack of immune system in healthy body tissues.In this work,two novel drug delivery systems were designed and synthesized based on the diselenide bond.These drug delivery systems can release both contained drugs and carriers which are also drugs in response to stimulis in inflammatory lesions,realizing the treatment of two specific inflammatory diseases(hyperuricemia and rheumatoid arthritis).This study is divided into the following two parts:1.Hyperuricemia is a metabolic disease caused by abnormal metabolism of purine and/or uric acid,and its incidence is increasing yearly.The excessive intake of high-purine foods,abnormal metabolism of purines,and the decline of kidney function may all lead to the occurrence and progress of high blood uric acid.Hyperuricemia can lead to the accumulation of urate crystals in the joints and tissues nearby,causing gout and other complications.At present,there is no effective long-term treatment for blood uric acid control.Based on this,we designed and synthesized a small molecule drug delivery system based on diselenide bonds for the treatment of hyperuricemia.The system V@Fx Se Se Fx consists of two parts:carrier which is self-assembled by small molecules formed by febuxostat connected via diselenium bonds,and the loaded drug valdecoxib,an inhibitor of cyclooxygenase 2,to achieve the effect of combined therapy.After being injected into the hyperuricemia model mouse,V@Fx Se Se Fx can remain long retention in mouse,and the diselenide bond can be broken in response to the high concentration of reactive oxygen in the system inflammation,leading to the dissociation of the system,thereby triggering the release of the two drugs to treat hyperuricemia.Compared with the model group,the V@Fx Se Se Fx treated group significantly reduced the blood uric acid levels of mice by 34.5%,and also significantly down-regulated the levels of tumor necrosis factor-α,interleukin-1β and interleukin-6 by44.0%,45.3% and 50.1%,respectively.V@Fx Se Se Fx alleviated the damage of kidneys in mice induced by high uric acid levels.The urea nitrogen and creatinine levels of the V@Fx Se Se Fx treated group were significantly reduced by 38.9% and 31.3%,and the degree of renal interstitial fibrosis was also greatly reduced.V@Fx Se Se Fx can inhibit the production of uric acid and the secretion of pro-inflammatory cytokines,which not only reduces the kidney damage caused by high uric acid levels,but also effectively relieves system inflammation,therefore has a good therapeutic effect on hyperuricemia.2.Rheumatoid arthritis is a common chronic systemic autoimmune disease.The human body’s immune system mistakenly attacks its own normal joints,other tissues and organs,and at the same time produces high concentrations of reactive oxygen species,which induce joint damage and chronic inflammation,eventually leading to progressive disability and systemic complications.At present,rheumatoid arthritis cannot be cured completely.Based on this,we designed and prepared a polymer drug delivery system based on diselenide bonds for the treatment of rheumatoid arthritis.The polymer carrier is formed by connecting the hydrophilic main chain chondroitin sulfate and the hydrophobic side chain cholesterol with diselenide bonds to form an amphiphilic polymer,which can self-assemble into nanoparticles.After loading the two kinase inhibitors tofacitinib and SP600125,the drug delivery system(TS@CSSeSeChol)can be used for combined therapy of RA.Injected into the collagen-induced arthritis(CIA)model mouse,TS@CSSeSeChol can accumulate in the CIA inflamed joints,where high concentration of reactive oxygen species leads to the cleavage of the di-selenium bond,thereby triggering the release of two kinase inhibitors.Compared with the model group,the serum tumor necrosis factor-α level in the TS@CSSeSeChol treated group was reduced by 58.3%.The joint clinical scores of the mice in the TS@CSSeSeChol treaed group were reduced by 72.7%,and the thickness of the hind paws were also significantly reduced by 76.3%.In the mouse cycle-running experiment,the sports ability of the mice in the TS@CSSeSeChol treated group was also significantly increased by 138%.TS@CSSeSeChol can also reduce joint destruction and cartilage loss in the CIA model mice and has a joint protective effect.Under the combined therapy of tofacitinib,SP600125 and chondroitin sulfate,TS@CSSeSeChol protected cartilage and joints by inhibiting the expression of related pro-inflammatory cytokines,thereby alleviating arthritis and reducing joint damage,and eventually leads to the high efficacy for CIA mouse therapy.