Design And Synthesis Of Inorganic Nanozyme And Its Application For Tumor Therapy

The rapid development of nanoenzymology has opened up a new path for the cancer diagnosis and treatments.Chemodynamic therapy(CDT)is a treatment that nanozymes catalyze the Fenton or Fenton-like reaction of H2O2 in the tumor microenvironment(TME)to generate reactive oxygen species(ROS)for inhibiting the growth of tumor cells.Common ROS includes hydroxyl radical(·OH),singlet oxygen(1O2),hydrogen peroxide and superoxide radicals,etc.Previous studies have shown that high concentrations of ROS can induce tumor cell apoptosis or even necrosis through oxidative stress.According to the inherent characteristics of the tumor microenvironment,herein,three strategies were proposed for the cancer treatment,i.e.,increasing the O2 concentration,H2O2 concentration,and reaction temperature of TME Correspondingly,three new types of nanozymes were designed and constructed to enhance the generation of ROS in the tumor area,and detailed theranostic performance and biological effects were investigated.The main research contents are listed as follows:(1)The construction of MnOx-based nanozyme CHHP and its enhanced photodynamic therapy for tumor.Mesoporous silica nanoparticles(MSNs)have been extensively applied as a promising carrier in biomedical application due to their distinctive structure with tuneable function.According to the different affinity characteristics of the surfactant trimethoxyoctadecylsilane(C18TMS)in different solvents(i.e.,the state of "on" in ethanol while "off" in water),an intelligent "on/off"strategy was developed to synthesize a kind of MnOx-based nanozyme,which were loaded with two different guest-components(e.g.,MnOx and Ce6)inside.The obtained Ce6/MnOx@HMSNs-PEG(CMHP)shows T1-weighted magnetic resonance imaging(MRI)performance to the over-expressed H2O2 and weak acidic pH in the TME.Furthermore,by using the catalase-like activity of MnOx to catalyse H2O2 in TME for generating O2,the CMHP nanozyme coud alleviate the problem of hypoxia in the tumor area,and further accelerate the generation of singlet oxygen(102)upon laser irradiation for enhancing the PDT effect when combined with Ce6.This strategy of site-specific controlled loading of bifunctional guest molecules within hollow mesoporous silica structure is expected to provide the material support for new methods of cancer diagnosis and treatment.(2)Construction of Prussian blue-based nanozyme GOx@HMPB for enhancing tumor synergistic chemodynamic and phototheamal therapy.The relatively low concentration of H2O2 derived from TME always presents limited therapeutic efficiency of CDT.In order to take advantage of the high metabolic characteristics of glucose in the tumor area,glucose oxidase(GOx)was successfully loaded into hollow mesoporous Prussian blue nanoparticles(HMPB).On the one hand,GOx can oxidize glucose to generate more H2O2.On the other hand,under the condition of partial acidity and a certain concentration of H2O2,HMPB could undergo Fenton reaction to produce·OH.Meanwhile,the obtained GOx@HMPB could produce higher concentration of·OH with increased_H2O2 and enhanced-temperature upon NIR irradiation,realizing efficient and effective treatment of 4T1 tumor model.The successful construction of GOx@HMPB nanozyme provides a practical solution for synergistic treatment of CDT and photothermal therapy(PTT),showing potential promising in the clinical transformation of HMPB.(3)Construction of mesocrystal structured Fe3O4 nanozyme enabling self-reinforceing synergistic chemodynamic and low magnetic hyperthermia therapy.Fe3O4 nanoparticles(NPs)with distinctive magnetothermal and nanozyme activity possess important application potentials in CDT and magnetocaloric therapy(MH).Magnetite(Fe3O4)nanoparticles(NPs)have been extensively explored in non-invasive cancer treatment,e.g.,magnetic hyperthermia(MH)and CDT.Herein,hollow Fe3O4 mesocrystals(MCs)are constructed via a modified solvothermal method.Owing to the distinctive magnetic property of mesocrystalline structure,Fe3O4 MCs show excellent magnetothermal conversion efficiency with a specific absorption rate(SAR)of high up to 722 w·g-1 at the Fe concentration of 0.6 mg·mL-1,much higher than that of Fe3O4 polycrystals(PCs)of the same size.Moreover,Fe3O4 MCs also exhibit higher peroxidase(POD)-like activity than that of Fe3O4 PCs,which may ascribe to higher ratio of Fe2+/Fe3+and more oxygen defects in the Fe3O4 MCs.By using the heating behavior of Fe3O4 MCs under an alternating magnetic field(AMF),Fe3O4 MCs can instantly enhance CDT by producing more detrimental ·OH with low H2O2 concentration in TME.Meanwhile,such boosted reactive oxygen level reduces the expression of heat shock protein(HSP),thus enabling low-temperature(43?)mediated MH for improving treatment effect and reducing side effects caused by high fever.The treatment model based on only single component of Fe3O4 MCs to achieve a highly efficient synergistic CDT and MH offers a novel strategy for the development of simpler and more effective tumor treatmentsThis thesis provides new ideas for increasing the ROS concentration in the tumor area,which improve the production of ROS by increasing the O2 concentration,H2O2 concentration and reaction temperature in the tumor area,respectively,further promoting the clinical transformation of new type of nanozymes in treatment of tumors.