Construction Of Hollow Mesoporous Silica Modified With Smart Responsive Polymers And Their Application In Drug Delivery

Disease is an extremely complex process.In many cases,the transition from health to disease is a process from quantitative change to qualitative change.The abnormal life activity process that occurs is due to the disorder of homeostasis under the action of a certain cause,and triggers a series of changes in metabolism,function,and structure,manifested as abnormal symptoms,signs and behaviors.A disease is an abnormal life activity process which is due to the disorder of homeostasis after the body is damaged by the cause of the disease under certain conditions.With the development of science and technology,many diseases have been completely eradicated.However,there are still many diseases,such as diabetes,cancer,etc.,which still have a great threat to human life and health.The intelligent drug delivery system,which can control the release of drugs according to microenvironment is considered to be an extremely promising treatment method for the disease.Compared with traditional therapies,such as oral and injection drugs,the intelligent drug delivery systems they can reduce potential toxicity and increase the utilization of drugs,thus reducing the harm to the patient’s body.Here,we construct hollow mesoporous silica modified with smart responsive polymers system that can automatically regulate drug release according to the microenvironment in vivo pathology for drug delivery.The specific work is summarized in the following three parts:1.First,glucose-responsive poly（3-acrylamidophenylboronic acid）polymer was synthesize by reversible addition fragmentation chain transfer polymerization（RAFT）method and modified on the surface of hollow mesoporous silica nanoparticles（HMSNs）prepared by template method.The anti-diabetic metformin drug was encapsulated in hollow mesoporous silica nanoparticles.Microneedles were prepared with polyvinylpyrrolidone（PVP）as the substrate and integrated glucose-sensitive drug-loaded hollow mesoporous silica nanoparticles by a template through a two-step method.The in vitro response release performance of glucose-sensitive drug-loaded hollow mesoporous silica nanoparticles was studied,and the results showed that they have obvious glucose-sensitive release properties.By testing the mechanical properties of the microneedles,the results showed that the microneedles have sufficient strength to penetrate the skin.Using fluorescent Rhodamine 6G（R6G）as a model drug instead of metformin,the penetration ability,solubility and drug response release characteristics of the microneedles were determined by laser confocal microscopy（CLSM）.The results showed that the microneedles can easily penetrate into skin tissue and dissolves within 30 several minutes.Moreover,the microneedles can achieve good drug release in the skin tissue of diabetic SD rats,while almost no release in the skin of healthy SD rats.Using streptozotocin（STZ）-induced diabetic mouse models to study the hypoglycemic effect of the prepared microneedles,the results showed that the prepared microneedles have a good hypoglycemic effect.The above results indicated that the prepared microneedles integrated with glucose-sensitive hollow mesoporous silica nanoparticles loaded with metformin have great application value in the transdermal treatment of diabetes.2.A diblock block copolymer,poly[4-（4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl）benzyl acrylate]-b-poly[2-（dimethylamino）ethyl methacrylate]（PPBEM-b-PDM）with pH and H₂O₂dual responsiveness,was synthesized by RAFT.Then the copolymer was modified onto the surface of HMSNs prepared by template method.The anti-diabetio metformin and glucose oxidase drugs were encapsulated in HMSNs to yield drug-loaded nanoparticles.Microneedles were prepared with PVP as the substrate to integrate the pH and H₂O₂responsive drug-loaded HMSNs by a template through a two-step method.The stimulation release characteristics of pH and H₂O₂responsive drug-loaded HMSNs in vitro were studied.The results showed that they have obvious H₂O₂,pH and glucose-sensitive release properties as well as variable release properties under varying glucose concentrations.By testing the mechanical properties of the microneedles,the results showed that the microneedles have sufficient strength to penetrate the skin.Using fluorescent R6G as a model drug,the penetration ability,solubility and drug response release characteristics of the microneedles were assessed by CLSM.The results showed that the microneedles can easily penetrate into skin tissue and dissolves,and can achieve good drug release in the skin tissue of diabetic SD rats,while almost no release in the skin of healthy SD rats.Using STZ-induced diabetes mouse model to study the hypoglycemic effect of the prepared microneedles,the results showed that the prepared microneedles have a good hypoglycemic effect.The above results indicated that the prepared microneedles integrated with pH and H₂O₂responsive hollow mesoporous silica nanoparticles loaded with metformin and glucose oxidase have great application potential in the transdermal treatment of diabetes.3.Then the nanocarriers used in previous section was applied to encapsulate the anticancer drugs doxorubicin hydrochloride and curcumin to evaluate the controlled drug release on the basis of cancer.The in vitro response release performance of pH and H₂O₂responsive drug-loaded hollow mesoporous silica nanoparticles was studied.The results showed that they have obvious pH,H₂O₂sensitive release and can accelerate the drug release rate in the presence of both pH and H₂O₂and improve the cumulative amount of drug released.Taking Hela cells as the research object,the cell uptake of pH and H₂O₂responsive drug-loaded HMSNs in vitro was characterized by CLSM.The experimental results showed that the drug-loaded nanoparticles can be swallowed by tumor cells and release drugs.In addition,Hela cells were used to test the in vitro cytotoxicity of drug-loaded polymer modified HMSNs.The results showed that it has the highest toxicity exposed to light(430 nm,20 m W cm^-2)after 30 min.The above results indicated that the prepared pH and H₂O₂sensitive hollow mesoporous silica nanoparticles loaded with anticancer drugs doxorubicin hydrochloride and curcumin have high application value in the delivery of anticancer drugs and the treatment of cancer.