PH-responsive Aminotriazole Doped Metal Organic Frameworks Nanoplatform Enables Self-boosting ROS Generation Through Regulating The Activity Of Catalase For Chemo/Chemodynamic Combination Therapy

Multifunctional nanocarriers(MNDs)have been widely used in chemotherapeutic drug delivery and in combination with multiple therapeutic modalities.Zeolite-like imidazole framework(ZIF)material is a kind of metal-organic framework(MOFs),and its unique p H responsiveness and good biocompatibility make it a good material for nano-drug delivery systems.Chemical kinetic therapy(CDT),as an emerging therapeutic method,has attracted much attention due to its unique reactive oxygen species(ROS)generation mode.However,it has some defects in tumor treatment,such as low ROS generation efficiency and poor efficacy of monotherapy.Therefore,how to improve the efficacy of CDT treatment is still a hot research topic.In this study,based on zeoloid imidazole skeleton(ZIF-8),2-methylimidazole(2-min)in ZIF-8 was partially replaced by 3-amino-1,2,4-triazole through group substitution,and part of Zn2+ in ZIF-8 was replaced by Cu2+.The anticancer drug doxorubicin(Dox)is then loaded into the resulting nanoion void.Finally,through ion coordination,hyaluronic acid(HA)was modified onto the surface of the nanometer ions to construct a nanometer drug delivery system with tumor targeting,CDT and chemotherapy combined therapy,and improved CDT therapeutic effect.The main research contents of this paper include:(1)Synthesis and characterization of DOX@Cu/ZIF-8 and Cu-MOF: Two kinds of nanocrystalline ions /ZIF-8 and Cu-MOF were synthesized by different methods,and the morphology and size of the nanoparticles were characterized by scanning electron microscopy and projection electron microscopy.Compared with Cu-MOF,DOX@Cu/ZIF-8 is more suitable as a nanomaterial for drug loading.(2)Synthesis and characterization of HA-MAF@DOX: In this study,a 3-AT-doped Cu/ZIF-8 nanocrystalline drug carrying system modified by hyaluronic acid and loaded with DOX was synthesized.The morphology and size of the final nanometer ions were characterized by scanning electron microscopy and transmission electron microscopy.In addition,the loading rate and release of DOX were measured by ultraviolet photometry.The Zate potential of nanometer ions was measured by DLS.The statistical results show that the particle size of HA-MAF@DOX nanoparticles is about 300-400 nm and its Zate potential is-18.1 m V.(3)Extracellular characterization of HA-MAF@DOX: we measured the p H responsiveness and ROS production efficiency of nano-ions outside the cell.The results show that HA-MAF@DOX can be rapidly degraded under acidic conditions,releasing loaded DOX,etc.Moreover,the ROS production efficiency of this nanoparticle is significantly higher than that of Cu2+ alone,which can be used for CDT treatment.(4)HA-MAF@DOX in vitro targeting and p H responsiveness: The intracellular expression of Fe nanoparticles was determined by flow cytometry and laser confocal microscopy.Both methods showed comparison with normal cells.Ox nanometer ion has specific targeting to tumor cells,and rapidly degrades and releases its loaded DOX in tumor cells.(5)The cytocompatibility,cytotoxicity and apoptosis of HA-MAF@DOX: The cytocompatibility and cytotoxicity of HA-MAF@DOX were determined by MTT assay.The apoptosis induced by HA-MAF@DOX was determined by flow cytometry.The results showed that HA-MAF@DOX had good cytocompatibility.Compared with DOX treated cells,HA-MAF@DOX has lower lethality to normal cells and higher lethality to tumor cells,indicating that nano-particles can improve the killing ability of tumor and reduce the toxic and side effects of DOX on normal cells.(6)HA-MAF@DOX intracellular ROS production: We observed intracellular ROS production with different nanometer ions by laser confocal microscopy.The results showed that HA-MAF@DOX significantly improved the ROS production efficiency compared with Cu/ZIF-8 nanometer ions,indicating that 3-AT in nanometer ions can effectively improve the ROS production efficiency of nanometer ions in tumor cells and improve the killing efficiency of CDT.To sum up,this study used ZIF-8 as carrier,introduced Cu2+ ion and 3-At through group substitution,and modified the surface of nanoparticles with HA,and successfully constructed the drug carrying system of HA-MAF@DOX nanoparticles.HA-MAF@DOX Nanoions can effectively target tumor cells,reduce the toxic and side effects of normal cells,and improve the killing ability of nanoparticles to tumor cells;The 3-AT group can inhibit catalase activity,improve the therapeutic effect of CDT,and realize the combination therapy of chemotherapy and chemodynamic therapy.