Construction And Antitumor Activity Of Multimodal Therapy Based On Glucose Oxidase

Glucose oxidase（GOX）is an ideal endogenous oxidoreductase for cancer starvation therapy.It can react with intracellular glucose and oxygen（O₂）to generate hydrogen peroxide（H₂O₂）and gluconic acid,which can cut off the nutritional source of cancer cells,thereby inhibiting the proliferation of cancer cells.This process also leads to increased acidity and increased hypoxia to further regulate the tumor microenvironment.Therefore,GOX opens up new possibilities for the multimodal treatment of tumor treatments and the elaborate design of multifunctional nanocomposites.Designing a multi-mode intelligent release targeted drug treatment system based on the specific differences between the tumor environment and the normal physiological environment,not only achieves the synergy and promotion of multiple single treatment modes,but also overcomes various shortcomings brought by the single treatment mode.The natural GOX coupled with biocompatible inorganic silicon materials can not only be safely delivered to the tumor department,but the triggered multimodal therapy can also effectively treat cancer.First,a GOX-induced enhanced p H response drug delivery system based on hollow mesoporous silica as a carrier,and the realization of a multimodal treatment method synergistic with chemotherapy and starvation therapy for tumor treatment.Second,based on nanocarriers with ferric oxide as the core and mesoporous silica as the carrier,externally coupled GOX triggers chemodynamic therapy combined with chemotherapy in a multimodal treatment mode with enhanced tumor starvation induction.We have designed a new HMSN-based drug delivery system to increase acidity and treat tumors through a variety of treatments,and encapsulated by a p H-sensitive polyelectrolyte layer.As a typical anticancer drug,DOX is loaded inside HMSN and has excellent killing effect on tumors.GOX was introduced outside the HMSN through grafting.In the cellular environment,it can catalyze the oxidation of glucose to produce toxic H₂O₂ and gluconic acid,effectively reduce the p H value of tumor cells,and consume oxygen and nutrients（glucose）in tumor cells,thereby achieving the purpose of hunger therapy.Here,we creatively use GOX as a p H-jumping agent to further lower the p H of the tumor environment and stimulate rapid drug release.Lower p H can greatly promote the decomposition of PEM,and its outermost positive charge is designed to target cancer cells overexpressed by negative charges.Transmission electron microscopy and scanning electron microscopy characterizations proved that we successfully synthesized DOX/GOX@HMSN-PEM with a uniform size of about 180 nm.In vitro experiments show that GOX can effectively promote drug release,and DOX/GOX@HMSN-PEM has a higher drug loading rate and stability.Its excellent cell uptake performance was obtained by confocal laser scanning microscope（CLSM）.And found that it has strong toxicity and promote apoptosis of cancer cells.We designed a new type of multimodal treatment for efficient cancer treatment:tumor starvation triggers a synergy between chemodynamic therapy and chemotherapy.Fe₃O₄nanoparticles（Fenton reaction catalyst）and anoxic prodrug tilapamine（TPZ）were loaded in mesoporous silica nanoparticles（MSN）,and then GOX was grafted onto the surface to prepare a multi-layer nanoparticles（TPZ/Fe₃O₄@MSN-GOX）with model therapeutic function.Logically,glucose oxidase（GOX）deprives tumor cells of nutrients（glucose and oxygen）for starvation therapy,while amplifying abnormal tumor expansion（increased acidity,increased hypoxia and increased H₂O₂ concentration）.Specifically,increasing the acidity can accelerate the release of iron ions and improve the Fenton reaction efficiency.As H₂O₂ concentration increased,ROS levels were detected to increase,which enhanced chemokinetic treatment.Increased hypoxia is programmed to activate hypoxic prodrugs（TPZ）for tumor-specific chemotherapy.Therefore,multimodal therapy is specifically designed for the tumor microenvironment,and has obtained effective abnormal magnification and high therapeutic effects and achieved satisfactory antitumor effects.