Biomimetic Construction And Performance Of Mesoporous Silica Drug Delivery System

Chemotherapy plays an important role in cancer treatment.Unfortunately,the drugs for chemotherapy often cause damage to normal cells and tissues during cancer treatment.Therefore,construction of cancer cell targeted drug delivery system（DDS）has been considered as an effective strategy for"precise"killing of cancer cells,thus reducing the side effects of drugs.Mesoporous silica nanoparticles（MSN）have attracted growing attention as drug carriers in recent years due to their high drug loading capacity,strong adaptability and easy surface modification.Nevertheless,MSN still has the potential to cause biosafety,long blood circulation and insufficient specific targeting issues,etc.,limiting their applications in clinical practice.In this thesis,MSN loaded with doxorubicin（DOX）has been surface modified by coating with mussel mimetic adhesion protein polydopamine（PDA）,achieving a DOX·MSN@PDA with the capacity to prevent the free release of DOX from mesoporous channels.Then,a cell membrane mimetic polymer（PMEN）and a targeted ligand have been successively anchored onto DOX·MSN@PDA surface,offering MSN with biological safety,targeting and drug controlled release ability.It provides a new strategy for the construction of chemotherapeutic drug carrier.The main research contents of this paper are as follows.（1）Preparation and properties of MSN carriers modified with mussel adhesion protein mimetic PDA.MSN synthesized via interfacial method is loaded with DOX and surface modified with PDA coating,successively,achieving DOX·MSN@PDA with particle size of 105.1 nm.Its pore size of pore volume peak is reduced from 5.1 nm to 3.0 nm.DOX·MSN@PDA has a drug loading rate of 12.9%.Its drug release rate is 16.3%in PBS solution with p H 7.4 for 96 h,which is decreased by 73.5%compared with DOX·MSN,demonstrating good slow releasing capacity.By contrast,the drug release rate is as high as92.8%in PBS solution with p H 5.0.This research offers a guideline for the subsequent construction of DDS with good performance.（2）Construction and properties of cell membrane mimetic modified MSN drug delivery system.A cell membrane mimetic copolymer PMEN containing phosphorylcholine group and active ester group was synthesized,and aminofolate FA-NH₂was synthesized.And by preparation research of successively grafting with dicarboxylic PEG,anchoring PMEN and coupling FA on the surface of MSN@PDA,DOX·MSN@PDA@PEG-FA/PMEN drug delivery system and its blank carrier were constructed and characterized.The uptake rate of MSN@PDA@PEG-FA/PMEN carrier by He La cells is 5.06 times higher than L929cells,indicating a significant targeting effect.The drug release rate of DOX·MSN@PDA@PEG-FA/PMEN drug delivery system in PBS solution with p H 5.0 for 96 h is decreased to29.3%,which is 68.4%lower than that of DOX·MSN@PDA.The toxicity of DOX·MSN@PDA@PEG-FA/PMEN to L929 cells(IC₅₀=12000μg/m L)is 3200 times lower than that of free DOX(IC₅₀=3.7μg/m L),while its toxicity to He La cells(IC₅₀=9.5μg/m L)is similar to that of free DOX(IC₅₀=4.4μg/m L).（3）Construction and properties of smart MSN drug delivery system.Amino folic acid containing disulfide bond FA-S-S-NH₂was synthesized.And by preparation research of successively anchoring PMEN,grafting 3,3’-disulfide dipropionic acid（DDA）and coupling FA-S-S-NH₂on the surface of MSN@PDA,DOX·MSN@PDA@PMEN/DDA-S-S-FA drug delivery system and its blank carrier were constructed and characterized.The uptake rate of MSN@PDA@PMEN/DDA-S-S-FA carrier by He La cells is 5.15 times higher than that of L929 cells,suggesting an outstanding tumor cell targeting performance.The drug release rate of DOX·MSN@PDA@PMEN/DDA-S-S-FA is only 28.7%in PBS solution with p H 5.0 for 96 hours,but it reached 68.5%in simulated cancer cell cytosol（PBS solution with p H 5.0 and 10 m M GSH）,shows good responsiveness to drug release environmental.Its toxicity to L929 cells is very low(IC₅₀=8000μg/m L),but the toxicity to He La cells(IC₅₀=2.5μg/m L)is higher than that of free DOX(IC₅₀=4.4μg/m L)by57%,shows high killing efficiency to cancer cells.（4）Construction and properties of multifunctional MSN drug delivery system with dual targeting and smart-drug-release.By simultaneous coupling FA and c RGD targeting ligands at the chain ends of DDA molecules containing disulfide bonds,DOX·MSN@PDA@PMEN/DDA-FA/c RGD drug delivery system and its blank carrier were constructed and characterized.The uptake rate of He La cells to MSN@PDA@PMEN/DDA-FA/c RGD carrier is 5.48 times higher than that of L929 cells,and the targeting selectivity to He La cells is better than that of MSN@PDA@PMEN/DDA-S-S-FA carrier.The drug release rate of DOX·MSN@PDA@PMEN/DDA-FA/c RGD in simulated cancer cell cytosol environment was increased to 71.4%,and its IC₅₀for L929 cells is improved to 9000μg/m L,IC₅₀for He La cells was 2.3μg/m L.It can be seen that its drug release rate in cancer cells and toxicity to cancer cells are higher than that of DOX·MSN@PDA@PMEN/DDA-S-S-FA drug delivery system.Therefore,DOX·MSN@PDA@PMEN/DDA-FA/c RGD drug delivery system has the advantages of low biological toxicity,dual targeting function of tumor cells,intelligent drug release function in tumor environment and high killing efficiency to He La cells,indicating a good application prospect in the field of anticancer drug.