Dissolving Polymeric Microneedles With Nanocarriers For Sustained Anti-Inflammatory In The Therapy Of Psoriasis

Psoriasis is a chronic inflammatory skin disease of erythema and scales,which seriously affects the quality of life for patients.Methotrexate(MTX),as an immunosuppressant and antimetabolite,has been widely used in the treatment of psoriasis,while the side effects caused by the injection and oral greatly limit its clinical application.Thus,many efforts have been made to develop safer and more effective ways to deliver MTX.Microneedles(MNs),a new device for transdermal drug delivery,have attracted widespread attention.MNs can effectively pierce the stratum corneum to deliver drugs without touching the nerve by its micron-sized needle tips,which not only avoids the first-pass effect by oral administration but also avoids the pain and infection by the injection,thus the MNs can improve patient compliance.Dissolving MNs have attracted enormous attention owing to their safety,convenience,and large loading capacity of drugs.Nevertheless,the MTX loaded-dissolving MNs are unable to release MTX in a sustained manner,and a substantial amount of MTX will be absorbed by the blood vessels,resulting in a low drug utilization rate and unsatisfactory therapeutic effects.Aiming at solving this problem,this thesis provides a feasible method: combining the MNs with elaborate drug-loaded nanoparticles which can strengthen the controlled release of MTX.In this thesis,we have demonstrated the fabrication of two different kinds of nanoparticles-loaded MNs for the delivery of MTX and psoriasis therapeutics:1.Construction of dissolving MN patch that can sustainably release MTX for the treatment of psoriasis.For the problem of rapid drug release by dissolving MNs,we load the MN with hybrid drug-loaded nanoparticles.First,we synthesize hollow mesoporous silica nanoparticles(HMSN).Subsequently,we load the MTX into HMSN by solvent volatilization(MTX@HMSN),and then the positively charged chitosan is coated on the surface of MTX@HMSN via electrostatic interaction.The obtained nanoparticles(MTX@HMSN/CS)can release MTX in a sustained way for 6 days and also exhibited the strongest cytotoxicity to Ha Ca T cells.Finally,the MTX@HMSN/CS-loaded MNs were fabricated by a micro-molding process.The MTX@HMSN/CS loaded MNs can effectively penetrate the skin of imiquimod(IMQ)-treated mice,and the ability of MTX@HMSN/CS MNs to relieve the inflammation improved by 10% compared with the control group,which is due to the sustained release of MTX by MTX@HMSN/CS MNs prevents the drug from being absorbed into the blood vessels.The strategy of combining hybrid drug-loaded nanoparticles with microneedles not only increased the drug utilization but also greatly reduced the frequency of administration,which provides great potential and prospects in the delivery of MTX.2.Construction of MN patches loaded with gelatinase-sensitive drug-loaded nanoparticles.To obtain an MN system that can deliver MTX more accurately according to the development of psoriasis,we first explored the correlation between inflammation and the expression of biomarkers.The significant expression of metalloproteinase-2(MMP-2)was observed at the lesion,and the expression degree is positively correlated with inflammation.Based on the fact that MMP-2 can effectively degrade gelatin,we constructed a new hybrid drug-loading MN for the controlled delivery of MTX in response to MMP-2.HMSN was utilized as the nanocarrier,and then the surface of HMSN was coated with gelatin through a low-temperature-mediated gel process,followed by the crosslinking via glutaraldehyde.The gelatin-coated HMSN was further used to load MTX,forming the MTX@HMSN/gel nanoparticles.The gelatin coating can protect the drug from leaking,and it can be hydrolyzed by MMP-2 at the skin lesion to open the mesoporous of HMSN and release MTX.The release process of MTX for the hybrid nanocarrier shows that the accumulative release increases in the presence of gelatinase so that the release rate of MTX can be well controlled.Finally,we embed the gelatinase-sensitive drug-loaded nanoparticles into the MNs for efficient delivery of MTX.We believe that the MN patch will improve the on-demand treatment of psoriasis in future clinic treatment.