Functionalized Nanomaterials Improve Tumor Microenvironment For Enhanced Photodynamic And Chemodynamic Therapy

Malignant tumor(cancer)is one of the principal diseases that threaten human health,and its morbidity remain high.How to cure cancer effectively is an important research topic in the field of medicine,pharmacy and chemistry.Traditional chemotherapy,radiotherapy and surgery have been widely used in clinical applications,but they have disadvantages such as inefficiency,low specificity,and serious side effects,so the efficacy of traditional therapies for tumor is not ideal.In recent years,some new modalities have emerged for cancer therapy and made great progress,such as photodynamic therapy(PDT)and chemodynamic therapy(CDT).The emerging tumor therapy method has the advantages of high therapeutic efficiency,good selectivity and low side effects.PDT and CDT rely on the generation of reactive oxygen species(ROS)to kill cancer cells,such as singlet oxygen(¹O₂),superoxide anion(O₂^·-)and hydroxyl radical(·OH).A certain amount of ROS can lead to irreversible oxidative damage of nucleic acids,proteins and mitochondria,which in turn affects their function and finally induces apoptosis of tumor cells,achieving the purpose of inhibiting tumor growth.However,the intrinsic biological properties of tumor microenvironment,such as hypoxia,limited hydrogen peroxide(H₂O₂)concentration and high levels of glutathione(GSH),seriously restrict the therapeutic efficacy of PDT and CDT.PDT for cancer is that photosensitizer can absorb energy and reach to excited state upon irradiation,and then transfer the energy to the surrounding oxygen molecules(O₂)to generate ¹O₂,which can be employed to kill tumor cells.O₂ is one of the most critical factors in PDT,which is directly related to the effect of PDT,therefore the hypoxia limits its efficacy.CDT is a treatment method that uses strong oxidative·OH generated by Fenton reaction or Fenton-like reaction in situ to kill tumor cells,and ultimately eliminate the tumor.H₂O₂ as a substrate for Fenton or Fenton-like reactions plays an important role in CDT,so the limited H₂O₂ content hinders its therapeutic effect in tumor microenvironment.In addition,overexpression of GSH in tumor microenvironment,as an intracellular antioxidant,can react with reactive oxygen species such as ¹O₂ and·OH,protecting cells from oxidative damage caused by reactive oxygen species.Thereby,the therapeutic effect of PDT and CDT is reduced.The above therapies have their intrinsic defects,and the complexity of the tumor microenvironment,which makes it difficult to inhibit tumor growth with a single tumor treatment method.Thus,the combination of multiple treatment methods to achieve tumor synergistic therapy has attracted wide attention.Synergistic therapy can not only conquer the deficiency of monotherapy,but also weaken the side effects caused by treatment,thus greatly enhancing the therapeutic effect.Recently,with the rapid development of nanoscience and nanotechnology,nanomaterials have been widely used in biomedical fields.Nanomaterials have special optical properties,adjustable morphology and size,and easy surface modification.Therefore,various functional groups or targeted groups can be modified on nanomaterials to achieve different properties.According to the above characteristics of nanomaterials,the surface of nanomaterials can be connected with antitumor drugs and molecules with specific response to tumor microenvironment,realizing effective treatment of tumors.Among them,nanomaterials with photothermal conversion ability,photosensitization effect,enzyme-like activity and catalytic performance provide new methods and sights for solving the existing problems in the application of PDT and CDT,thereby they have been widely used in the study of tumor PDT and CDT.In this dissertation,based on the functionalized nanomaterials and characteristics of tumor microenvironment,we developed novel therapy systems to enhance the therapeutic effects of PDT and CDT.The main research contents are as follows:1.The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of PDT.To solve this problem,a multifunctional composite(Ce O₂-PEG-Ce6-GOx),which combines polyethylene glycol(PEG)functionalized cerium oxide nanoparticles(Ce O₂)with photosensitizer chlorin e6(Ce6)and glucose oxidase(GOx),is reported for generating O₂ within the tumor microenvironment by the dual-path H₂O₂-modulated ways to ameliorate hypoxia,thereby enhancing the efficiency of PDT/starvation synergistic therapy.This process is realized based on the dual enzyme-like activity of Ce O₂.The first modulated way is to transform the superoxide anion(O₂^·-)into H₂O₂ by the superoxide dismutase-like activity of Ce O₂.The second modulated way is to decompose glucose into H₂O₂ through the catalysis of GOx.Subsequently,H₂O₂ generated from the above dual modulated ways can further produce O₂ via the catalase-like activity of Ce O₂.Moreover,glucose consumption hinders nutrient supply,realizing tumor starvation therapy caused by the depletion of glucose.Both in vitro and in vivo experimental results showed that the strategy improved tumor hypoxia through catalytic reaction and enhanced the efficacy of photodynamic/starvation synergistic therapy.2.The limited H₂O₂ content and slow Fenton reaction rate in tumor microenvironment restrict the therapeutic effect of CDT to some extent.To solve this problem,a novel curative strategy which combines functionalized multiwalled carbon nanotubes(MWNTs)with Fe₃O₄ and GOx(PEG-MWNTs-Fe₃O₄-GOx),is proposed to increase Fenton reaction,thereby achieving a mild hyperthermia-enhanced enzyme-mediated tumor CDT.The GOx can catalyze the conversion of glucose into gluconic acid and H₂O₂,which can elevate acidity and H₂O₂ content of the tumor microenvironment,so as to promote Fe₃O₄-based Fenton reaction to produce a myriad of·OH,inducing tumor cell death.Furthermore,we use the mild hyperthermia produced by the MWNTs and the theory that temperature rise expedites the kinetics of a chemical reaction,increasing Fenton reaction rate to improve the productivity of·OH per unit time.Therefore,the therapy platform,mild hyperthermia-enhanced GOx-mediated CDT,provides an effective treatment for tumor.3.The high level of GSH in tumor cells could consume·OH,greatly reducing the curative effects of CDT.To solve this problem,a multifunctional composite(Au NPs-PEG-Fc)is developed by integration of polyethylene glycol(PEG)functionalized gold nanoparticles(Au NPs)and ferrocene(Fc),which can induce both Fenton reaction and GSH depletion to amplify cellular oxidative stress,enhancing CDT efficacy.The Au NPs with the glucose oxidase-like activity can catalyze glucose into H₂O₂,while the as produced H₂O₂ is subsequently catalyzed by Fc to generate·OH by Fenton reaction,inducing tumor-cell death.More importantly,Au NPs-PEG-Fc reduces cellular GSH to minimize the·OH elimination,synergistically amplifying oxidative stress and thereby enhancing the efficacy of CDT.Therefore,this research provided a therapeutic strategy simultaneously augmenting ROS production as well as inhibiting ROS elimination to break the redox homeostasis,enhancing the efficacy of ROS-mediated tumor CDT.