Construction Of Several Stimuli-responsive Inorganic Nanomaterials And Their Performance For Tumor Theranostics

Cancer,as a major public health problem,is a major threat to human health and life,so it is crucial to overcome this challenge.In recent years,the booming development of nanotechnology has provided new opportunities for cancer treatment.The development of nanotechnology-based cancer therapies tops the list of five frontier cancer research themes focused by the Koch institute for integrative cancer research at MIT.Among them,inorganic functional nanomaterials can specifically respond to endogenous/exogenous stimuli to initiate treatment and thus compensate for the many drawbacks of traditional tumor treatment methods such as incomplete diagnostic information,difficulty in eradication,and serious side effects.Here,several inorganic nanomaterials with high efficiency and low toxicity have been constructed to enable fluorescence imaging,photoacoustic imaging,photothermal therapy,and sonodynamic therapy under exogenous stimulation,as well as chemodynamic therapy and glutathione responsive therapy under endogenous signal stimulation in the tumor microenvironment.The dissertation focuses on the functionalized design and biomedical application of inorganic nanomaterials for“integration of diagnosis and treatment”,and the results are summarized as follows:First,in order to solve the problems of multiple laser sources,inadequate therapeutic efficacy and poor efficacy in conventional photothermal therapy,dendritic mesoporous silica（DMSN）was used to coat the down-conversion nanoparticles,and then ultrasmall oxygen-deficient molybdenum oxide nanoparticles（Mo O_x NPs）were loaded inside.The down-conversion nanoparticles emit bright NIR-II emissions（1060 nm and 1300 nm）when excited by 808 nm laser,achieving deep-tissue fluorescence imaging.Combined with their inherent computed tomography and magnetic resonance imaging effects,the diagnostic agent could offer more comprehensive information about the tumor lesions.The loaded Mo O_x nanoparticles could be specifically activated by abundant hydrogen peroxide in the tumour microenvironment,thus generate highly toxic singlet oxygen through the Russell mechanism,they also have capabilities of glutathione depletion and oxygen compensation.In addition,Mo O_xnanoparticles exhibit remarkable PTT efficiency with a photothermal conversion efficiency of51.5%,and the generated heat can further synergized with chemodynamic therapy.As a result of the synergistic therapeutic effect of photothermal and chemodynamic therapy,the nanocomposite significantly inhibited the growth of malignant tumors,with a tumor suppression rate of 84.8%in cervical cancer.This“all-in-one”nanocomposite provides a new strategy for deep tumor imaging and treatment.Second,the mitochondria-targeting molecules were modified on the surface of cubic Cu₃VS₄ nanoparticles to construct“phonon-liquid”CVS nanoparticles,which could solve the complicated synthesis of nanocomposite in the above study and further improve the therapeutic efficacy of photothermal therapy.The CVS nanoparticles possess excellent photothermal conversion efficiency（32.78%）and ideal photoacoustic imaging capability under 808 nm laser irradiation.Density functional theory calculations reveal the three-fold degeneracy occurring at the top of valence band and a relatively low diffusion barrier of Cu ions within the lattice,improving the thermoelectric performance of the material at room temperature with thermal conductivity as low as 0.3 W m^-1 K^-1.Under temperature gradient,CVS nanoparticles can catalytically yield superoxide radicals and induce the oxidation of endogenous NADH through the thermoelectric effect.When CVS nanoparticles accumulate inside mitochondria,endogenous NADH is depleted and the function of complex I is competitively inhibited,which in turn impairs oxidative phosphorylation and reduces the ATP synthesis,thereby down-regulating the expression of heat shock proteins,and ultimately the heat resistance of tumor cells is mitigated.In addition,under the tumor microenvironment,CVS nanoparticles can catalytically generate hydroxyl radicals from endogenous hydrogen peroxide for chemodynamic therapy.Cellular and In vivo experiments showed that the synergistic apoptosis of biocompatible CVS nanoparticles could effectively inhibit tumor growth with a tumor suppression rate of 98.28%in breast cancer.This work lays the theoretical foundation for the application of photothermoelectric materials in the field of biomedical treatment and also validates the great potential of mitochondrial metabolism modulation in the field of cancer therapy.Third,to address the problem of limited penetration depth of exogenous light stimulation in tissues,a two-dimensional Bi₂Mo O₆-PEG nanoribbons（BMO）triggered simultaneously by external ultrasound stimulation and endogenous glutathione stimulation was constructed as the piezoelectric sonosensitizer to mediate a two-step enhancement sonodynamic therapy.During the first step of enhancement process,the BMO nanoribbons can undergo a redox reaction with endogenous glutathione to yield GSH-activated GBMO nanoribbons in the tumor region.Meanwhile,the oxygen-deficient sites produced inside GBMO nanoribbons could serve as electron trapping sites to restrain the recombination of electron-hole pairs,thus resulting in a higher generation efficiency of ultrasound-triggered generation of reactive oxygen species.In the second step process,the efficiency of sonodynamic therapy is amplified by the exogenous ultrasound stimulation.The two-dimensional GBMO nanoribbons with piezoelectric properties can efficaciously utilize the large pressure induced by bubble collapse to induce polarizationand create a built-in electric field.The sono-generated electrons and holes are separated by a powerful driving force of piezo-potential and migrate to the opposite surfaces,and the conduction band and valence band edge of GBMO bend closer to O₂/·O₂^-and H₂O/·OH standard potentials,which are favorable for the generation of reactive oxygen species.Due to the two-step enhanced sonodynamic process,the BMO NRs exhibited excellent anti-tumor efficiency in vitro and in vivo,with a 96.6%tumor suppression rate in cervical cancer.Besides,considering the remarkable X-ray attenuation capability of the Bi element,BMO nanoribbons can also be used as a high-performance CT contrast agent to guide therapy.In conclusion,this work not only offers a new option for improving the efficacy of sonodynamic therapy,but also demonstrates the great potential of two-dimensional piezoelectric materials as sonosensitizers.