| Cancer is an insurmountable problem worldwide and places a heavy burden on patients and their families.Chemotherapy is still one of the main means of treating tumours,yet most chemotherapeutic drugs are subject to low bioavailability,poor selectivity,severe toxic side effects and drug resistance,which ultimately lead to the failure of tumour chemotherapy.In order to address the limitations of chemotherapeutic drugs,active targeting nano-delivery systems have been developed.Active targeting nano-delivery systems use ligand-receptor,antigen-antibody or other forms of molecular recognition between the nano-delivery system and target tissues or cells to deliver drugs to specific locations,which can further enhance the uptake of drugs by tumour cells,enhance the therapeutic effect of drugs and significantly reduce the side effects of the body compared to passive targeting,thus achieving increased efficacy and reduced toxicity.Metal organic frameworks(MOFs).also known as porous coordination polymers,are formed by the self-assembly of metal ions and organic ligands through coordination bonds.They are widely used in catalysis,energy storage and separation,and have become a hot research topic as drug carriers in recent years.Zeolitic imidazolate framework-8(ZIF-8)is a new type of porous material belonging to the MOFs category,consisting of Zn2+ and 2-methylimidazole ligands,with simple synthesis strategy,easy functionalization,high loading capacity and pH-responsive degradation,and is a very promising new drug carrier.Active targeting ligand modification on the surface of ZIF-8 carriers can enhance the antitumour activity of delivered drugs while reducing the toxic effects on normal tissues.The main research contents and the results are as follows:Doxorubicin(DOX)loaded ZIF-8 nanoparticles were successfully prepared by the"one pot stirring method",and glycyrrhetinic acid(GA)was modified on its surface to construct a DOX delivery system targeting GA receptors.The morphology of nanoparticles was observed by SEM and TEM,and it was found that PEG-GA@ZIF-8@DOX is spherical in shape with uniform particle size.The hydration particle size of PEG-GA@ZIF-8@DOX is 236.37±0.21 nm,and the Zeta potential is-6.52±0.29 mV.XRD confirmed that the nanoparticles had standard crystal structure.The FT-IR,UV,and BET results confirmed the successful loading of DOX and the successful modification of GA ligands.The drug loading of DOX in PEG-GA@ZIF-8@DOX is approximately 11.22±0.87%,and the final release in acidic environments is 57.73%.The hemolysis rate of PEG-GA@ZIF-8@DOX is lower than 5%at various concentrations,and preliminary verification shows that the biocompatibility of the nano formulation in vivo is good.The human hepatoma cell line HepG2 was used to examine the in vitro cellular uptake as well as lysosomal escape properties.The CCK-8 method was used to study the in vitro cytotoxicity of the drug,and the results showed that PEG-GA@ZIF-8@DOX had significantly better uptake than DOX and could successfully escape from the lysosome and enhance the antitumor activity of DOX.The anti-tumor effect of PEG-GA@ZIF-8@DOX was investigated by establishing H22 tumor-bearing mouse model,and the results showed that PEG-GA@ZIF-8@DOX could not only enhance the anti-tumor effect of DOX,but also reduce the side effects caused by DOX,and the H&E staining results showed that PEG-GA@ZIF-8@DOX had no obvious toxicity to the major organs of mice.PEG-FA@ZIF-8@BAN,a baicalin(BAN)nano-delivery system with ZIF-8 as a carrier and folic acid(FA)targeting modification,was prepared.The morphology of the nanoparticles was observed by SEM and TEM,and the uniform particle size of PEGFA@ZIF-8@BAN was found.The hydrated particle size of PEG-FA@ZIF-8@BAN was measured by DLS to be 176 ± 8.1 nm with a zeta potential of-23.83±1.1 mV and good dispersion.The XRD results showed that PEG-FA@ZIF-8@BAN has a standard crystalline structure.FT-IR,UV,and BET characterization results showed successful loading of BAN and modification of PEG-FA.The loading efficiency of BAN was as high as 41.45±1.43%and the drug release was 78.60%in acidic environment(pH=5.0)and only 11.03%in neutral environment(pH=7.4).The results of in vitro cellular experiments showed that PEG-FA@ZIF-8@BAN could significantly enhance the killing effect of BAN on MCF-7 cells,and the FA-mediated targeting could make the nanoparticles better taken up by tumor cells and promote the production of reactive oxygen species(ROS)by tumor cells,which greatly enhanced the killing effect of the drug on tumor cells.4T1 tumor-bearing mouse model was established to evaluate the in vivo antitumor activity of PEG-FA@ZIF-8@BAN.The results of the study showed that the system could significantly enhance the proliferation inhibition and induce apoptosis of tumor cells in solid tumors of breast cancer without causing significant pathological damage to major organs.No significant abnormalities were also found in the liver and kidney function indices of all groups of mice,indicating the low toxicity of the system in mice.In summary,this work focuses on the design of ligand-receptor active targeting drug delivery systems based on metal-organic framework materials.In this thesis,the ZIF-8 material,which is acidic environment-responsive degradable and biocompatible,was selected as the drug carrier,and the drug delivery system was constructed with simple synthesis method,mild reaction conditions and good dispersion and stability.It is a novel and highly effective anti-tumor nano platform that can address the problems of low bioavailability,poor selectivity and serious adverse reactions of some drugs,and provide a "potency and toxicity reduction" idea for anti-tumor chemotherapeutic drugs with strong toxic side effects or tumor therapeutic candidates of natural origin,and also broaden the scope of application of MOFs in biomedical field. |
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