Design Of Organic/inorganic Composite Drug Delivery System And Its Glucose Responsiveness

Controlled release drug delivery system can make the drug release at appropriate time or place,reducing the possibility of early release,so as to obtain better drug effect.Among them,glucose-responsive drug delivery systems have been extensively studied in recent years.By giving the drug delivery system glucose responsiveness,the amount of drug released depends on the content of glucose in the release medium.When the glucose concentration increases,the amount of drug released will be improved accordingly to achieve controlled release of the drug.Compared to injecting insulin directly,this method is more intelligentized,not only reduce the number of doses,but also prevent the occurrence of hypoglycemia and keep blood glucose stable.The current glucose-responsive drug delivery system has problems such as difficult removal of by-products,slow response speed,and large size of the drug carrier.Based on these,we designed two organic/inorganic composite glucose-responsive drug delivery systems by using glucose oxidase（GOx）and 4-carboxyphenylboronic acid（CPBA）as glucose sensitive units,ZIF-8 and ZnO as drug carriers.The specific research contents and experimental conclusions are summarized as follows:1.Preparation and research of GOx-Au@ZIF-8 glucose-responsive drug delivery systemGOx-Au@ZIF-8 nanoparticles were obtained by a simple co-precipitation method,using zinc nitrate hexahydrate as the zinc source,dimethylimidazole as the organic ligand,and adding GOx and gold nanoparticles（AuNPs）.The successful preparation of GOx-Au@ZIF-8 was proved by SEM,TEM,FTIR,TG,nitrogen adsorption and desorption,and the electrochemical method proved that it has glucose responsiveness and hydrogen peroxide responsiveness.Furthermore,the hypoglycemic drug metformin（MET）was added during the preparation process to obtain a drug loading of 80 mg/g.The drug-loaded GOx-ZIF-8 and GOx-Au@ZIF-8 are immersed in glucose solutions of different concentrations for sustained drug release.When the release medium does not contain glucose,only a small amount of MET is released within 24 h.When the glucose concentration was 1 mg/m L,the drug release increased obviously.When the glucose concentration was 4 mg/m L,the cumulative drug release rates of GOx-Au@ZIF-8 and GOx-ZIF-8 reached（86.1±3）%and（79.5±2.7）%,respectively,indicating that the drug delivery system has Good glucose responsiveness.In addition,the introduction of AuNPs removes the by-product H₂O₂generated in the reaction system and generates O₂.O₂ can further participate in the reaction of glucose oxidase catalyzed by glucose,thereby forming a closed-loop drug delivery system.Using He La cells as a model,the cytotoxicity of the drug delivery system was measured by the CCK-8method.The results show that when the sample concentration is 50μg/m L,the cell survival rate is still above 90%,which indicates that the drug delivery system has a good performance.Biocompatibility,has the potential as a glucose-responsive drug delivery system.2.Preparation and research of SA/CPBA/ZnO glucose-responsive drug delivery systemAminated mesoporous ZnO nanoparticles were prepared by a simple solvothermal method,using zinc acetate dihydrate as the zinc source and dopamine hydrochloride as the raw material.CPBA/ZnO nanoparticles were obtained by combining 4-carboxyphenylboronic acid（CPBA）activated by EDC/NHS on ZnO nanoparticles through amidation reaction.Using the principle that phenylboronic acid can be combined with adjacent diols,the surface of CPBA/ZnO nanoparticles was further modified with sodium alginate（SA）to obtain glucose-responsive SA/CPBA/ZnO nanoparticles.A series of characterizations of aminated ZnO,CPBA/ZnO,SA/CPBA/ZnO were carried out by SEM,XRD,FTIR,TG,nitrogen adsorption and desorption method,Zeta potential and other methods.The results showed that CPBA and SA successfully bound to the surface of aminated ZnO.The drug-loaded SA/CPBA/ZnO was dispersed in glucose solutions of different concentrations for sustained drug release.When there was no glucose in the release medium,only a small amount of drug was released within 12 h.When the glucose concentration is 1 mg/m L,the cumulative release rate of the drug within 12 h increases significantly.When the glucose concentration reaches 4 mg/m L,more drugs are released,and the release amount within 12 h reaches（71.8±2.8）%,which shows that the drug delivery system has good glucose responsiveness.Using He La cells as a model,the cytotoxicity of the drug delivery system was measured by the CCK-8 method.When the concentration of SA/CPBA/ZnO was 40μg/m L,the cell survival rate remained above 80%,indicating that SA/CPBA/ZnO has good biocompatibility and has the potential as a carrier for glucose-responsive drug delivery systems.