The Application Of Novel Metallic Oxide/Hydride Nanomaterials For Cancer Theranostics

The tumor microenvironment(TME)is the internal environment of a solid tumor in which tumor cells could survive and proliferate.The characteristic features of the TME include hypoxia,acidic pH values,endogenous H2O2,excess levels of GSH,and over-expressed enzymes.The TME usually promotes tumor growth and metastasis,as well as be also responsible for the therapeutic resistance and treatment failure.In recent years,with the development of nanoscicence and nanotechnology,the design and construction of multifunctional nanomaterials for TME modulation and enhanced cancer therapy has attracted wide attention.These nanomaterials with special physical and chemical properties can efficiently modulate TME,such as neutralizing acidic pH value,overcoming tumor hypoxia,and decreasing excess ROS for enhanced cancer therapy.Therefore,in this doctoral dissertation,we synthesize a series of TME-responsive nanomaterials and evaluate the performance of these nanoplantforms for enhanced cancer therapy,aiming to develop effective and biosafe therapeutic strategies.The main achievements are summarized as follows:1.Core-shell TaOx@MnO2 nanocomposites to overcome tumor hypoxia for enhanced radiotherapy.In this work,we synthesized core-shell TaOx@MnO2 nanostructures by growing MnO2 nanoshells on the surface of TaOx nanoparticles.In this nanosystem,we employed MnO2 as the catalyst to decompose H2O2 into O2 and Ta as a high-Z element to concentrate X-ray radiation energy.The obtained TaOx@MnO2-PEG nanoparticles could not only efficiently concentrate X-ray radiation energy inside the tumor,but also improve tumor oxygenation by decomposing H2O2 in the tumor.As a result,an exceptional synergistic RT sensitization effect was achieved with TaOx@MnO2-PEG to completely eliminate tumors under a low X-ray irradiation dose.2.Endogenous GSH-activated MnMoOx nanoprobe for PA imaging of tumor.In this work,we synthesized bimetallic oxide MnMoOx nanorods via the thermaldecomposition method.With GSH incubation,the color of MnMoOx would change from colorless to blue,owing to the reduction of MoⅥ in the initial MnMoOx to Mov by GSH.Utilizing good absorbance of the GSH-activated MnMoOx nanoprobe,PA imaging of tumor and photothermal tumor ablation were successfully realized.3.The depletion of GSH by ultrasmall MnWOx nanoparticles for enhanced sonodynamic therapy.In this work,we synthesized ultrasmall oxygen-deficient bimetallic oxide MnWOx nanoparticles.The MnWOx-PEG nanoparticles with a high valence of W6+showed a unique capability of GSH depletion,which would further enhance SDT efficiency by preventing GSH-mediated clearance of ROS.Such oxygen-deficient MnWOx-PEG sonosensitizers with efficient US-triggered ROS generation capability combined with its GSH depletion performance could offer excellent sonodynamic therapeutic outcomes in tumor treatment.4.FeWOx nanozyme-based ratio-metric nanoprobe for ratio-metric PA imaging of endogenous H2O2.In this work,we synthesized a new type of peroxidase-like nanozyme(FeWOx)and then employed them as the nanocarrier and catalyst to fabricate H2O2-activated PA nanoprobe.In this nanoprobe,TMB and IR 780 were co-loaded on this nanosheet surface.Using this nanoprobe,we could realize H2O2-activated ratio-metric PA imaging of tumors and inflammation with high sensitivity and selectivity.5.Multivalent FeWOx nanoreactors for TME modulation and enhanced radiotherapy and immunotherapy.In this study,we synthesized multivalent FeWOx nano sheets as intelligent cascade bioreactors.These FeWOx nanoreactors could simultaneously consume endogenous H2O2/GSH and amplify oxidative stress of the tumors,cooperating with X-ray could significantly improve cancer RT,as well as working together with immune checkpoint blockade could elicit robust immune responses to defeat tumors.Our work highlighted the broad application of the multi-functional nanoreactor in TME-regulation and tumor therapy.6.TiH1.924 nanodots to overcome tumor hypoxia by the photothermal effect for enhanced sonodynamic therapy.In this study,we for the first time exfoliated TiH1.924 powders into ultrasmall nanodots via the liquid-phase exfoliation technology.The as-made TiH1.924 nanodots with black color possessed high near-infrared absorption.Then,using this photothermal agent to mildly heat the tumor and then overcome tumor hypoxia,we could achieve effective combined cancer therapy with the presence of TiH1.924 nanodots.In summary,in this doctoral dissertation,based on the characteristic features of the TME,we have designed and constructed a series of TME-modulating nanoplatforms for relieving tumor hypoxia,decreasing excess GSH/ROS,and overcoming immunosuppression,further enhancing the response tumors for various therapeutic strategies.Based on these performances,we have proposed a number of different strategies for combined cancer therapy with promising therapeutic performance.