Study On Treatment Of Rheumatoid Arthritis With Polypeptide Nano-Selenium And Functional Nano-Ruthenium

Rheumatoid arthritis?RA?is a chronic autoimmune inflammatory disease associated with persistent polyarticular synovitis,cartilage destruction and even loss of joint function.The inflammatory process occurs mainly in synovial tissue,and activated macrophages produce inflammatory cytokines that cause persistent inflammation,joint swelling,bone erosion,and cartilage damage.This can lead to pain,swelling,stiffness and dysfunction.Once the disease reaches a certain degree of severity,it must undergo joint replacement surgery,which seriously affects people's normal life and reduces the quality of life.Although significant progress has been made in the clinical treatment of RA,long-term use of anti-rheumatic drugs still has many drawbacks,including high doses,high frequency,poor selectivity,severe toxic and side effects.In particular,frequent medication use may cause dysfunction in major organs such as the heart,liver,and kidney.For the above problems,it is necessary to develop new therapeutic drugs to avoid non-specific systemic administration,at the same time,to promote the therapeutic efficacy and reduce the side effects by improving the accumulation of drugs in the diseased tissues.Nanopharmaceuticals have unique properties such as the accumulation by active or passive targeting at the lesion site,efficient drug loading,intelligent sustained drug release,and prolonged circulatory dynamics.It is a good strategy to improve the therapeutic effect of RA and reduce the side effects.Chapter1:The outline and pathological features of rheumatoid arthritis?RA?are summarized.The current treatment strategies for RA are introduced and present the advantages of nanomedicine treatment compared with traditional therapeutic methods.It focuses on the current drug types for RA,their therapeutic efficacy,side effects.Particularly the strategies treating RA with nanomedicines,including active or passive targeting strategies,stimulation-responsive drug delivery systems,and the development and challenges of nano delivery systems for the treatment of RA.Finally,it explains the significance and purpose of this topic.Chapter2:Rheumatoid arthritis?RA?is a chronic autoimmune disease and there is a lack of effective treatments.Nitric oxide?NO?plays an important role in the inflammatory diseases,but the exact mechanism is not clear.We Selected ruthenium complexes[Ru?Phen?₂?4idip?]?ClO₄?₂?Ru?to induce the generation of NO in cells.SeNPs-PEG-RGD@Ru?Se@RuNPs?was prepared by modifying selenium nanoparticles with PEG,RGD and Ru.Se@RuNPs can promote the uptake by Human Umbilical Vein Endothelial Cells?HUVEC?and trace the internalization and biodistribution.Experiments showed that Se@RuNPs target the abundant neovascularization of inflammatory sites to induce NO and promote apoptosis of HUVEC and inhibit the growth of new vessels in local tissue.Moreover,NO activates autophagy by modulating signaling pathways related to AMPK?and mTOR,increaseing flux of autophagy,inhibiting activity of NF-?B-p65,and modulating levels of inflammatory cytokines.The exact mechanism of the inflammatory response regulated by NO is revealed.Histopathological analysis showed that Se@RuNPs effectively reduced synovitis,cartilage corrosion and inflammatory cytokine expression levels,achieving satisfactory therapeutic effects.These unexpected results provide an effective strategy for target treatment of RA.Chapter3:Rheumatoid arthritis?RA?is a chronic autoimmune inflammatory disease associated with persistent multiarticular synovitis,cartilage destruction,and even loss of joint function.An important feature of rheumatoid arthritis is the infiltration of inflammatory cells of the synovial membrane.However,the polarization type of macrophages plays an important role in the process of regulating inflammatory cells infiltration.Traditional therapeutic drugs such as dexamethasone,methotrexate and so on,their therapeutic target is not clear,the treatment cycle is so long and during treatment usually accompanied with obvious side effects,which severely limits drug application.Thus,we design and synthesize multifunctional nano-ruthenium,its photo-thermal and photo-acoustic imaging capabilities exert essential role for the diagnosis and treatment of rheumatoid arthritis.Using the special property of macrophages that can effectively reduce the pro-inflammatory cytokines level in inflamed tissues,firstly,the nano-system is targeted to macrophages at inflammatory tissues,then controls the drug release by photo-thermal responses to regulate the type of macrophage polarization?change M1 type to M2 type?.This strategy obviously improve the inflammatory microenvironment and achieve desired therapeutic effect.