Construction Of Deep Eutectic Solvent-antioxidant Mesoporous Silica-hydrogel And Its Non-invasive And Controlled Transdermal Delivery For Arthritis Treatment

Transdermal delivery of solid nanoparticles relies on both microneedle administration and subcutaneous injection,both of which can cause discomfort to patients,while in reported studies,it has been demonstrated that low eutectic solvent（DES）can be used to prepare mesoporous silica nanoparticles（MSNs）for transdermal delivery using hydrogen-bonded acceptor amino acids（AA）and hydrogen-bonded donor citric acid（CA）,which extends the MSNs drug delivery system for applications and provides a new strategy for the controlled and sustained delivery of nanoparticles.On this basis,functionalized mesoporous silica was formed by preparing cerium nanoparticles hybridized with MSNs and then loading methotrexate（MTX）,a drug for rheumatoid arthritis,onto the nanoparticles,which were then reacted with citric acid and arginine and carbomer 940 by co-heating to form a DES-MSNs-hydrogel system.The DES-MSNs-hydrogel prepared by this method has strong mechanical properties and high skin affinity,and the NPs have effective skin penetration through the"resistance"effect.Under dermal application,the hydrogel can drive rigid NPs through the skin in a non-invasive manner,resulting in sustained penetration and accumulation of MSNs at the RA site.Thus,the loaded MTX exerts a direct therapeutic effect,while cerium nanoparticles modulate the inflammatory microenvironment by scavenging ROS and promoting macrophage repolarization.In this way,a synergistic immunochemotherapy for RA is achieved.Thus,our work provides a new strategy for the multimodulation and controlled management of arthritis treatment.The main findings and results of this thesis include.1.Synthesis of functionalized MSNs and their ROS scavenging activity and preparation and characterization of DES-MSNs-hydrogel system:firstly,CeO₂nanoparticles were synthesized,followed by the synthesis of MSNs with CeO₂nanoparticles as the core and MSNs in its outer layer,forming a state of hybridization between CeO₂nanoparticles and MSNs,and showing good ROS scavenging ability for DPPH,hydroxyl radicals and superoxide anion,the scavenging ability was significant for three reactive oxygen species.Subsequently,the surface of this nanoparticle was modified with the hydrogen-bond donor CA and then encapsulated with the therapeutic drug MTX to finally form Ce@MSNs@MTX nanoparticles.It was prepared as DES-MSNs system by heating together with hydrogen-bonding acceptor Arg and hydrogen-bonding donor CA,and then DES-MSNs-hydrogel system was prepared by adding carbomer 940 together with co-heating.The successful synthesis of Ce@MSNs@MTX nanoparticles and the successful modification of CA onto Ce@MSNs@MTX to form MSNs-CA were demonstrated by using TEM,FTIR,BET,XRD,TG,DLS and zeta potential.The SEM-EDS,rheological tests and molecular dynamics simulations were used to investigate the DES-MSNs-hydrogel system.The basic physical properties,the system can highly disperse MSNs to make them uniformly distributed,and the stability of the whole system is much better than that of dispersing MSNs in water or hydrogel.2.DES-MSNs-hydrogel In vitro in vivo skin permeation experiments with DES-MSNs-hydrogels:In vitro permeation experiments were performed using fluorescence microscopy to observe the transdermal delivery ability of different samples and high performance liquid chromatography to determine the drug content in the diffusion cell.The results showed that the DES-MSNs-hydrogel system could penetrate deeper into the skin layer and to a greater depth than if the MSNs were dispersed in other media.Transmission electron microscopy also detected the presence of MSNs and elemental Si in the DES-MSNs-hydrogel group in the diffusion cell.When examining the permeation ability of different model skins（pig skin,rat skin and artificial membrane）,all of them had the highest MTX permeation and the strongest permeation ability in the DES-MSNs-hydrogel group.In the in vivo permeation experiments,we firstly administered the drug to a rat joint for a certain period of time and then executed it,and detected the signals of Si and Ce elements in the joint by biological scanning electron microscopy and energy spectroscopy,which proved that the MSNs could permeate through the skin into the joint.The time dependence of their penetration ability was then demonstrated by immunofluorescence.It indicates that mesoporous silica nanoparticles can successfully enter the body by DES-MSNs-hydrogel and exhibit time-dependent absorption properties.3.Study on the therapeutic effect of DES-MSNs-hydrogel on rheumatoid arthritis:A rat model of CIA was induced by bovine type II collagen to investigate the therapeutic effect of DES-MSNs-hydrogel joint topical administration on RA,and the results showed that the newly prepared hydrogel could significantly reduce the inflammatory factors TNF-α,IL-6,IL-3,and Caspase-1 levels in CIA rats.It showed that the prepared DES-MSNs-hydrogel had good permeability properties,and the cerium nanoparticles in MSNs promoted the conversion of macrophages from M1 to M2 after entering the skin,while methotrexate produced the effect of treating arthritis,and the two acted synergistically in order to achieve non-invasive treatment.4.Dermal safety evaluation of DES-MSNs-hydrogel:DES-MSNs-hydrogel does not cause toxicity to animal organs and does not cause physiological damage to animals after administration,proving its safety.In summary,a new DES-MSNs-hydrogel system was prepared by hybridizing CeO₂nanoparticles with MSNs and then loaded with MTX,and finally modified by CA to form a composite nanoparticle,which was then co-heated with citrate arginine carbomer 940.This system can be used for the treatment of rheumatoid arthritis through the strong skin permeability of DES and the stable intermolecular force between DES and MSNs,and provides a theoretical basis and data support for the future non-invasive treatment of rheumatoid arthritis through its local non-invasive drug delivery characteristics and good skin safety.It provides a theoretical basis and data support for future non-invasive treatment of rheumatoid arthritis.