Composite Vehicle Combined With Functional Polymer And MOF For Oral Delivery Of Diabetes Therapeutic Peptide

Diabetes,as a worldwide disease,requires for novel technology for development of therapeutic strategy.Oral insulin delivery has been explored and researched since the discovery of insulin.However,few products have been put into practical application.Despite of the obstacles for efficient oral peptide administration,hundreds of strategies for oral insulin or other diabetes therapeutic peptide delivery have been made by pharmaceutical factories and researchers because of its convenience and potential metabolism advantage.To realize the efficient oral peptide delivery,both of the protection of the peptide from the degradation in gastrointestinal environment and the enhanced absorption of peptide by intestine should be considered.In view of the particular requirement of the alimentary canal,we tried to use microspheres or pHsensitive capsules to resist the disintegration from the acidic environment in stomach,and took the advantage of the nanoparticle for further delivery through intestinal epithelium.We chose metal-organic frame(MOF)as the drug loading core,since it has uniform hierarchical mesoporous structure,which benefits the peptide loading and protection.Other functional polymer and molecule were also combined to MOF nanoparticles for the adjustment of the material stability,drug release and cellular uptake behavior.We combine the design above and try to realize the efficient oral peptide administration for diabetes treatment.The main content was summarized as following:MIL-100 nanoparticles were combined with mPEG-b-PLLA microspheres to form a composite vehicle for oral insulin delivery.MIL-100 inhered considerable drug loading content,and the further SDS modification strengthened the cellular uptake of the nanoparticle.The PLA microsphere was design for the protection of nanoparticle and insulin inside from the acidic environment in stomach.We adjust the size and morphology of the nano-vehicle and detect its properties.The cell uptake and transportation behavior of the vehicle were proved through the experiment based on Caco-2 cells.The results from the type I diabetes rats after oral administration proved the hypoglycemic effect.We chose NH2-MIL-101 as an efficient drug loading core,and used the method of surface free radical crosslinking to form a hydrogel shell on it to form the oral excendin4 carriers.The zwitterionic groups in the hydrogel shell helped the penetration of the mucus layer on the intestinal epithelial cells because of their pollution resistance.The pH-sensitive capsule was used here for intestine locating release,and the blowing agent inside would accelerate the unpack of the capsule the supply the motivation for the nano-vehicles.We focused on the construction and structure of the MOF-Gel system,and cultivated the Caco-2 cells and HT29-MTX-E12 cells to prove superiority of the zwitterionic modification in cellular transportation compared with shell with other charge.The results from the type ? diabetes rats after oral administration proved the efficiency of exendin-4 delivery and the further insulin secretion of insulin followed by the hypoglycemic effect.Based on the carrier design above,we tried to introduce Fe3O4 magnetic nanoparticle to the MOF-Gel system in order to take the advantage of magnetism for efficient oral insulin delivery.The Fe3O4 nanoparticle was used as a core,and MIL-101 was grown on it.We have tried varied method to balance the magnetic behavior and drug loading content.The materials were tested with cell and animal experiment to prove the possibility of magnetism method for oral insulin delivery.