Study On Tantalum-Based Hollow Mesoporous Nanospheres For Radiotherapy Sensitization Of Breast Cancer By Modifying Hypoxia Tumor Microenvironments

Cancer is a major threat to human health.Radiotherapy is one of the main clinical treatments,but its efficacy is limited in many ways,such as severe side effects and tumors hypoxia.Innovative methods are desiderated to improve radiotherapy effect.Tantalum(Ta)has been extensively utilized in clinical application with good biological compatibility due to its nontoxic and bioinert properties.Tantalum based nanoparticles has been used as radiosensitizer and CT contrast agent in several studies owing to its X-ray attenuation ability as a high-Z element.Therefore,in this dissertation,PEGylated hollow mesoporous TaOx nanospheres conjugated with CuS Nanocrystals(HMTCP)loaded with oxygen-saturated PFP have been successfully synthesized,which exhibited high photothermal efficiency,ability to concentrate irradiation energy,strong oxygen carrying capacity and good biocompatibility.Then,we further synthesized self-degrading hollow mesoporous organosilica nanospheres conjugated with Pt NPs and Au NPs loaded with Doxorubicin(HMOT@Pt@Au@Dox),which can catalyze hydrogen peroxide to oxygen andβ-D-glucose to hydrogen peroxide,self-degrading,targeting release doxorubicin in tumor microenvironment and further improving biocompatibility.The research process and results are summarized as following:Hollow mesoporous TaOx nanospheres(HMT)was synthesized via sol-gel method,then CuS nanocrystals was bond to the HMT through electrostatic adsorption to prepare hollow mesoporous TaOx/CuS nanospheres(HMTC).After functionalized with C18PMH-mPEG,oxygen-saturated PFP was loaded into the hollow cavity of PEGylated HMTC.The photothermal conversion efficiency(η)of HMTCP was 52.56%and oxygen may release from HMTCP@PFP@O2 under the irradiation of 808 nm NIR laser.Next,we investigated HMTCP and HMTCP@PFP@O2 in vitro,the results indicated that HMTCP have good biocompatibility.As a radiosensitizer,HMTCP@PFP@O2 has the capability to increase cellular oxygenation,thus enhance the ablation effect of radiotherapy on 4T1 tumor cells and inhibit their proliferation.Then,we investigated HMTCP and HMTCP@PFP@O2 in vivo.According to the quantitative data of biodistribution study,concentration of HMTCP in tumor site peaks at 24 h after intravenous injection.By using Hypoxyprobe(pimonidazole hydrochloride)in BALB/c mice bearing 4T1 tumors,it was found that NIR laser-triggered mild photothermal therapy or intravenous injection of HMTCP@PFP@O2 can improve tumor hypoxia.The in vivo studies showed that HMTCP@PFP@O2 combined with mild photothermal therapy and radiotherapy could almost completely inhibit tumor growth in BALB/c mice without obvious toxicity.Furthermore,we investigated the capability of HMTCP@PFP@O2 in enhancing CT imaging,ultrasound imaging,and photoacoustic imaging in vitro and in vivo.The result showed that the HMTCP@PFP@O2 were able to act as a contrast agent for multimode US/CT/PA imaging of tumors.The particle size of as-prepared HMTCP is about 107 nm,which is easy to concentrate in tumor sites,though may cause chronic side effects when accumulated in large quantities.Based on the synthesis process of HMTCP,self-degradable hollow mesoporous organosilica nanospheres(HMOT)was successfully synthesized via aforementioned method with slight modifications.then catalase-mimicking platinum nanoparticles and glucose oxidase(GOx)-mimicking gold nanoparticles were embedded within the HMOT to prepare HMOT@Pt@Au.After functionalized with C18PMH-mPEG,water-insoluble doxorubicin was loaded in HMOTP@Pt@Au,denoted as HMOT@Pt@Au@Dox.We found that platinum nanoparticles in HMOTP@Pt@Au can catalyze H2O2 to oxygen,while gold nanoparticles can catalyze β-D-glucose to hydrogen peroxide,further producing the catalytic substrate for platinum nanoparticles,accelerating the depletion of β-D-glucose in tumor cells.Furthermore,DOX-loaded redox-responsive HMOTP@Pt@Au can effectively release doxorubicin in 10mM GSH.Next,we investigated HMOTP@Pt@Au in vitro,the results indicated that HMOTP@Pt@Au has good biocompatibility.Similarly,HMOTP@Pt@Au could improve cellular oxygenation,thus enhance the ablation effect of radiotherapy on 4T1 tumor cells and inhibit their proliferation.By using Hypoxyprobe(pimonidazole hydrochloride)in BALB/c mice bearing 4T1 tumors,it was found that HMOTP@Pt@Au can improve tumor hypoxia.The in vivo studies showed that HMOTP@Pt@Au@Dox combined with radiotherapy could inhibit tumor growth in BALB/c mice without obvious toxicity.In this dissertation,the tantalum-based nanospheres as-synthesized combined with photothermal therapy and radiotherapy,achieving excellent theranostic efficiency.Based on the successful synthesis of HMTCP,we developed self-degradable hollow mesoporous organosilica nanospheres(HMOTP),which have synergistic therapeutic outcome in chemoradiotherapy and further improve biocompatibility.It is hoped that our work may further promote the research and application of tantalum-based nanomaterials in cancer treatment.