Construction Of DOX-loaded Cppper-based MOF Acid-sensitive Drug Delivery System And Its Anti-tumor Activity

Cancer is one of the important threats to human life and health in modern society.Solving and treating cancer is now a social consensus.However,traditional treatments for cancer only have a certain effect on early patients,and patients in the middle and late stages are often at a loss.Therefore,it is urgent to develop new treatment methods combined with traditional treatment methods to solve this problem.Tumor microenvironment（TME）is characterized by overexpression of glutathione（GSH）,high content of hydrogen peroxide（H₂O₂）,hypoxia and weak acidity of the environment.This complex environmental characteristics lead to drug resistance of tumor cells and continuous invasion and metastasis during growth.Therefore,regulating and improving TME is the key to inhibit and kill cancer cells.Chemodynamic therapy（CDT）,which treats tumors by regulating oxidative stress,is achieved by regulating and improving TME.The copper-based Fenton-like reaction with higher reaction rate in weak acid environment can further improve the effect of chemical kinetic therapy.Therefore,based on copper-based MOF,this paper constructs two acid-sensitive drug delivery systems for combined treatment of tumors.The main research contents are as follows:（1）A novel nanocatalytic platform Ca O₂@DOX@Cu/ZIF-8 based on Cu/ZIF-8 nanocarrier was synthesized for combined chemotherapy and chemodynamic therapy.Doxorubicin（DOX）was loaded onto calcium peroxide（Ca O₂）nanoparticles to form Ca O₂@DOX,which was then encapsulated in Cu/ZIF-8 to form Ca O₂@DOX@Cu/ZIF-8 NPs.In the slightly acidic tumor microenvironment,Ca O₂@DOX@Cu/ZIF-8NPs rapidly disintegrated and released Ca O₂,which reacted with water to produce H₂O₂ and O₂ in the tumor microenvironment.Cu/ZIF-8 released Cu²⁺and then reacted with H₂O₂ to produce highly toxic^·OH.The efficient accumulation and specific release of DOX and Cu²⁺in tumors make Ca O₂@DOX@Cu/ZIF-8 nanoparticles effectively inhibit tumor growth through synergistic effect.The samples were characterized by SEM,energy spectrum,potential particle size analyzer,UV-vis and Fourier transform infrared spectrometer.The results showed that Ca O₂@DOX@Cu/ZIF-8 NPs with an average particle size of 196 nm and DOX loading rate of 5.0 wt%were successfully synthesized.The release rate of Ca O₂@DOX@Cu/ZIF-8 NPs in aqueous solution at p H 5.5reached 85%.In vitro cytotoxicity experiments,when the concentration of Ca O₂@DOX@Cu/ZIF-8 NPs was 200μg/m L,the inhibition rate of HGC cells reached 87%.In vivo experiments in mice,when the tumor-bearing mice were injected for 14 days,the weight and volume of the tumors treated with Ca O₂@DOX@Cu/ZIF-8 NPs were the smallest compared with PBS,DOX and Ca O₂@Cu/ZIF-8,indicating that Ca O₂@DOX@Cu/ZIF-8 NPs can effectively inhibit tumor growth in mice.Ca O₂@DOX@Cu/ZIF-8 NPs showed excellent effects in the treatment of tumors with combined chemotherapy and CDT,which provided a new idea for the design of copper-based nano-drug delivery system for combined treatment of tumors.（2）In addition,a novel nano-drug platform PCN-224（Cu）@Ca O₂DOX@ZIF-8（PCDZ）was designed based on copper-based MOF（PCN-224（Cu））.Based on PCN-224（Cu）,Ca O₂@DOX was adsorbed on the surface of PCN-224（Cu）by the coordination of DOX and metal ions,and then ZIF-8 was encapsulated in the outermost layer of PCN-224（Cu）@Ca O₂@DOX by electrostatic adsorption to prepare PCDZ.It was characterized by SEM potential particle size analyzer,UV-vis and Fourier transform infrared spectrometer.The results showed that PCDZ NPs with an average particle size of 228 nm were successfully synthesized,and the drug loading rate of DOX was 4.6 wt%.In the in vitro anti-tumor activity study,when the concentration of PCDZ NPs was200μg/m L,the inhibition rate of PCDZ+NIR on Hep G2 cells reached90%.Therefore,at the cellular level,after introducing photodynamic therapy（PDT）into the nano-catalytic platform,the triple combination of CDT,PDT and chemotherapy further enhanced the killing effect on tumor cells.In summary,two copper-based nano drug delivery systems（Ca O₂@DOX@Cu/ZIF-8 nanoparticles,PCDZ nanoparticles）were designed in this work.Through characterization and related experiments,it was proved that the copper-based nano drug delivery system has excellent anti-tumor ability,which provides a new idea for related design.