PH-responsive And Tumor-targeting Self-assembled Nano-reagents For Photodynamic And Starvation Synergistic Antitumor Therapy

Malignant tumor is a serious threat to human health and life.Surgery,radiotherapy,chemotherapy and other methods are generally used to treat tumor in clinical practice.Due to low specificity and serious side effects,the therapeutic effect is not ideal.As a result,emerging tumor therapies,such as photodynamic therapy（PDT）,chemodynamic therapy（CDT）,and starvation therapy（ST）,have been widely concerned because of their high selectivity,low toxicity and high efficacy.However,the limited content of O₂ and H₂O₂ in tumor will affect the therapeutic effect to a certain extent.Studies have shown that grafted onto the surface of nanomaterials with antitumor drugs or biomacromolecules that specifically respond to tumor microenvironment can effectively treat tumors.Among them,nanomaterials with photosensitization,simulated enzyme activity and catalytic performance can solve the problems in the above treatment,and then are widely used in cancer treatment.Two self-assembled nanoparticles were designed and developed to enhance the therapeutic effect of PDT,CDT and ST.First,a pH-responsive polymer ligand,PIMA-mPEG-API-EDA-TCPP,was synthesized and then self-assembled with the Fe³⁺drive into a self-oxygenating and pH-induced charge-convertible nanoplatform（called Sp-NPs）for enhanced photodynamic therapy.Experiments have shown that Sp-NPs with charge transfer properties can change the surface charge from negative to positive in the extracellular environment of weakly acidic tumors,thus enhancing cell internalization.After entering acidic tumor cells through endocytosis,Sp-NPs is immediately detonated to activate the photosensitizing agent TCPP and release Fe³⁺,which can catalyze endogenous hydrogen peroxide（H₂O₂）to produce O₂,thus significantly enhancing tumor fluorescence imaging and reactive oxygen species（ROS）generation.Importantly,the nanoplatform demonstrated good cancer cell killing efficiency compared to free TCPP.Secondly,biomineralized nanoparticles（GOx-Fe@HA-Ce6）with double enzyme activity were prepared,which can regulate the glycolysis activity of tumorcells,provide oxygen,and increase the expression of H₂O₂ at the tumor site.To enhance the photodynamic,chemodynamic and starvation synergistic therapeutic effect.The nanoparticles first entered the tumor by specific binding of hyaluronic acid（HA）to CD44 overexpressed on the surface of tumor cells,and then were degraded by hyaluronase to lyse their structures.Firstly,glucose oxidase（GOx）can catalyze glucose to produce H₂O₂ and gluconic acid,which can not only regulate sugar metabolism at the tumor site,but also accelerate the Fenton reaction rate.Then,Fe-containing nanase catalyzes H₂O₂ to produce O₂,which can improve the glucose-consuming ability of GOx in nanoparticles and significantly enhance the production of ROS.The experiment shows that this strategy is expected to enhance the photodynamic,chemodynamical and starvation synergistic anti-tumor effect.