Inflammation Responsive Nanoparticles For The Effective Treatment Of Rheumatoid Arthritis

Rheumatoid arthritis(RA)is a complicated autoimmune disease,accompanied with severe chronic synovial inflammation and cellular infiltration.RA patients will experience joint swelling,cartilage damage,joint space narrowing and joint dysfunction,which can cause irreversible disability in severe cases.At present,the treatment of RA mainly focuses on delaying the disease progression and alleviating the symptoms of disease.With the development of nanotechnology and biomaterials,it has become an effective strategy for the treatment of RA to encapsulate the therapeutic drugs within nanocarriers and deliver them to the site of inflammation to achieve curative effects.Recent studies have found that nanocarriers could selectively target to the inflammatory site through the ELVIS effect,which can effectively reduce the dosage of drugs and minimize the side effects of drugs.However,conventional nanocarriers also have many shortcomings such as the uncontrolled drug release in inflammatory areas that limits the further application of nanocarriers in the treatment of RA.It is reported that the inflammatory site of RA patients has many pathological characteristics which are different from normal tissues,such as low pH and overexpression of matrix metalloproteinases(MMPs).Therefore,it is a feasible solution to overcome the above-mentioned shortcoming of nanocarriers to design a delivery vehicle that can maintain stability in circulation and release therapeutic drugs responsively at the inflammatory site.Therefore,we constructed an inflammationresponsive drug delivery system for the treatment of arthritis according to the special physiological environment of inflammatory sites.Here,we fabricated a MMPs-responsive nanoparticle by the co-assembly of TGMS and DSPE-PEG.The nanoparticles could remain stable in the blood circulation and avoid being cleared by the reticuloendothelial system because of the PEG on the surface of the nanoparticles;And the ester bonds of TGMS molecules can be cleaved by MMPs,allowing the therapeutic drugs to be released in time in the arthritic joints and exerting therapeutic effects.Results revealed that the MMPs-responsive nanoparticles had the average size of 122.40±2.79 nm with approximately spherical morphology.And the encapsulation rate of dexamethasone(Dex)was 95.52±0.50%.Moreover,the nanoparticles had high biocompatibility and colloidal stability.In vitro release experiment has proved that MMPs can significantly accelerate the drug release in inflammatory sites.The pharmacokinetic analysis showed that the drug-loaded nanoparticles greatly improved the bioavailability and half-life of Dex in plasma.In the rat adjuvant-induced arthritis model,the nanoparticles could promote the accumulation of drugs in inflamed joints significantly.And intravenous injection of Dex-loaded nanoparticles into arthritic rats could significantly reduce the degree of joint swelling and inhibit the production of inflammatory cytokines TNF-? and IL-1? in joint tissues,ultimately achieving effective treatment of arthritis.The release of drugs triggered by one single stimuli might suffer from the inadequate responsiveness,leading to the insufficient or delayed drug release.In order to increase the sensitivity of drug release at inflammatory sites and further improve the therapeutic effect in RA,in the second part of our study,we used 3-aminobenzeneboronic acid(PBA)as a linker to connect PEG-COOH and TGMS together to synthesize an amphiphilic polymer,which could form micelles through selfassembly in an aqueous solution.The newly formed borate ester is cleavable in the acidic condition and the TGMS segment contains a MMPs-cleavable bond.Therefore,the micelles formed from the PEG-PBA-TGMS conjugates would be responsive to acidic pH and overexpressed MMPs.Results showed that the critical micelle concentration of the dual-responsive micelle was about 19 ?g/m L.The average particle size of the micelle was 164.90±12.70 nm and it had a nearly spherical morphology.The encapsulation rate of Dex was 80.31±3.06%.In vitro stability experiments showed that the polymeric micelles had high biocompatibility and colloidal stability.In vitro MTT experiments and hemolysis experiments showed that the dual-responsive micelles had good biocompatibility.Furthermore,the Dex-loded micelles could release therapeutic drugs quickly under the stimulation of low pH and high expression of MMPs.In vivo imaging system demonstrated that obvious fluorescent signals can be observed at the inflamed joints after injection of fluorescein-loaded micelles into arthritis rats through tail vein.Results revealed that the dual-stimuli responsive micelles could preferentially accumulate in the inflammatory sites in arthritic model.After the intravenous administration of Dex-loaded dual-stimuli responsive micelles in arthritic rats,the joint swelling of arthritic rats and the level of TNF-?,IL-1? and IL-6 in joint tissues were significantly reduced.And the pathological condition at the inflammatory site were greatly improved.In summary,we constructed an inflammatory-responsive nanocarrier for the treatment of RA,which can preferentially distribute to inflamed joints.And the drugloaded nanocarriers could release therapeutic drugs in response to the inflammatory environment and ultimately achieving a remarkable therapeutic effect on arthritic rats.