Stimulus-responsive Multifunctional Nanoplatforms For Photodynamic And Chemodynamic Therapy Of Tumor

Malignant tumor has evolved to be a global health concern that threatens millions of people.One of the most critical challenges in cancer therapy is how to circumvent the side effect of therapeutic agents to normal tissues or cells.Although clinical trails represented by chemotherapy and radiotherapy may have certain efficacy,the accompaning side effects greatly affect the patient’s quality of life.In this context,a nano drug delivery system responive to endogenous stimuli of the tumor microenvironment（weakly acidic p H,hypoxia,overexpressed biomolecules,etc.）is expected to precisely eradicate tumor and minimize side effect.Moreover,with the goal of potent efficacy bearing in mind,reactive oxygen species generated by photodynamic therapy and chemodynamic therapy may be employed to effectively inhibit the growth and proliferation of tumor cells,achieving precise and effective cancer therapy.In this thesis,we constructed multifunctional drug delivery systems driven by endogenous stimuli for enhanced photodynamic and chemodynamic cancer therapy.The main contents are as follows:1.Size-Switchable Nanoparticles for Regulation of Tumor Microenvironment and Enhanced Photodynamic TherapyThe rapid growth and active metabolism of tumors give rise to a unique tumor microenvironment（TME）featuring abnormal blood vessels and excessive extracellular matrix（ECM）,which limits the transportation,retention and penetration of drugs,as well as subsequent therapeutic outcomes.In view of the low drug retention rate and poor permeability,a size-switchable therapeutic platform（denoted as T-PFRT）was built for enhanced photodynamic therapy.T-PFRT exhibited a core-satellite structure,where the linker peptide connecting core and satellite particles can be specifically cleaved by the overexpressed matrix metalloproteinase 2（MMP2）in TME,causing the structure disassociation and releasing the satellite particle for deep penetration.In the meantime,the core particle utilizing dendritic mesoporous silica to load transforming growth factor-β（TGFβ）signaling pathway inhibitor and oxygen-carrying hemoglobin was responsible for facilitating the deep diffusion of nanoparticles and elevating the therapeutic efficacy of satellite particle constructed by photosensitizer-loaded ferritin.In this regard,enhanced drug penetration contributed from size conversion and ECM remolding can be collaborated with TME normalization by TGFβinhibition and hypoxia relief,eventually inhibited the growth of primary tumor and prevented the formation of metastatic tumor.2.Zinc Peroxide@Mesoporous Silica Dual-Enzyme Nanoreactors for Gene-Chemodynamic Synergistic Therapy of CancerConstruction of an endogenous stimulus-responsive nano-drug delivery system by utilizing the physiological difference between tumor and normal tissues is one of the most effective routes to achieve precise treatment and avoid side effects on normal tissues.Based on this,we designed a zinc peroxide-mesoporous silica core-shell dual-enzyme nanoreactor to combine gene therapy and enhanced chemodynamic therapy.The Zn O₂@Fc DMSN@DNAzyme/GOx（ZFDG）nanoreactors were fabricated by modifying ferrocene（Fc）onto the surface of mesoporous silica-encapsulated zinc peroxide nanoparticles,followed by electrostatic adsorption of DNAzyme and glucose oxidase（GOx）in the pore structures.After internalization into tumor cells,the nanoreactors could release the zinc ions under the stimulation of intracellular acidic environment to activate DNAzyme,downregulating early growth factor-1（EGR-1）and inhibiting the proliferation of tumor cells by gene intervention.The delivered GOx and Fenton reagents created favorable conditions for Fenton reaction,thereby increasing the production of reactive oxygen species that could achieve enhanced efficacy of chemdynamic therapy.This program proposes a synergistic modality to combine precisely triggered gene therapy and enhanced chemdynamic therapy,which exhibits obvious anticancer effect and hold promise to inhibit the regrowth of tumor.