Study And Application Of Inorganic Nanomaterials In The Treatment Of Hypoxic Tumors

Affected by the rapid global population ageing and the ecological environment deterioration,malignant tumors with increasing incidence and mortality over time is one of the most important challenges of modern biomedicine.Compared with normal physiological tissues,malignant tumors exhibit various special physiological microenvironments,including weak acidity,oxygen deficiency,high concentration of reactive oxygen species,multiple overexpressed enzymes and reducing microenvironment,which are the main inducer of tumor metastasis and recurrence,seriously restricting the cure of tumors.It is particularly disturbing that the hypoxia in tumors is the crucial problem in the cure of tumors.The hypoxic microenvironment changes the survival state of the tumor by accelerating the variation and enhancing the adaptability and invasion ability of the tumor,thus significantly reduces the sensitivity of tumor tissues to the treatments that are heavily dependent on oxygen,such as radiotherapy,chemotherapy and photodynamic therapy.In addition,it increases the resistance of tumor,leads to an unstable and incomplete treatment,and induces serious consequences of tumor recurrence,metastasis,and erosion.Aiming at these problems,a series of multi-functional inorganic nanocomposites have been designed and synthesized in this thesis to improve the therapeutic effect of tumors by relieving the tumor hypoxic microenvironment.The specific work is detailed as follows:(1)In view of the low efficiency and heavily oxygen dependence of photodynamic therapy in hypoxic tumors,as well as the treatment induced further exacerbation of hypoxia that may promote tumor recurrence and metastasis,we have designed and synthesized a multi-functional diagnosis and treatment integrated nanocomposite with upconversion nanoparticles as the core and graphene nitrogen carbide as the photosensitizer.In this system,cerium oxide,acting as a linker between upconversion nanoparticles and graphene nitrogen carbide,can produce large amounts of oxygen by interacting with hydrogen peroxide to relieve the hypoxic condition in acidic tumors.Meanwhile,the stripped graphene nitrogen carbide nanoparticles can be uniformly dispersed in tumor cells and penetrate deep into the tumor.Stimulated by the external near-infrared light,upconversion nanoparticles display a photothermal effect to kill tumor cells,and further transform infrared light into blue-violet light,by which graphene nitrogen carbide is prompted to produce superoxide radical and hydroxyl radical,so as to destroy DNA and proteins in the tumor and induce tumor cell apoptosis.Moreover,gadolinium-based upconversion nanoparticles can be used to guide the location of tumors by MRI and computed tomography(CT),thus enabling precise treatment of tumor sites and reducing damage to other normal tissues.We believe that this treatment nanoplatform can effectively alleviate the hypoxic tumor microenvironment and enhance the effect of photodynamic therapy,which will play an active role in the future clinical practice.(2)Taking into account the issues like low efficiency and high toxic side effects of radiotherapy in the treatment of hypoxic tumors,we have designed and synthesized the Cu S@Ce O₂ nanoparticles with copper sulfide nanoparticles as the matrix material and cerium dioxide as the adhesive.These rough nanoparticles show a spindle structure that is favorable for uptake by tumor cells.After being injected into the body,the nanoparticles can be enriched in tumor due to the enhanced permeability and retention(EPR)effect of the tumor,and then interact with hydrogen peroxide in the tumor microenvironment to produce large amounts of oxygen and alleviate the hypoxic condition of the tumor tissue.Meanwhile,the internal copper sulfide nanoparticles can be gradually stripped off and infiltrated into the deep tissue of the tumor.The tumor tissues with improved oxygen environment are more sensitive to radiotherapy,revealing a superior therapeutic effect.Additionally,combined with oxygen-independent photothermal therapy,tumor cells can be effectively killed to inhibit the tumor recurrence and metastasis.(3)Inducing tumor cell apoptosis and necrosis is the main approach of modern biomedical treatment for tumors,however,it is always difficult to achieve the desired effect due to an increasing risk of tumor drug resistance,recurrence and metastasis.Therefore,we adopted ferroptosis,a new type of cell death that is different from apoptosis and necrosis of tumor cells,to promote the death of tumor cells,and achieve the purpose of curing tumor under the synergistic effect of chemotherapy and radiotherapy.In this system,iron oxide(Fe₂O₃),as the matrix material,can provide sufficient Fe³⁺and Fe²⁺for promoting the intracellular ferroptosis,and produce a large amount of oxygen to supply cells in this process.The tumor tissues with improved oxygen environment are more sensitive to radiotherapy,revealing a superior therapeutic effect.Furthermore,in order to improve the water solubility and stability of nanoparticles,we modified the surface of Fe₂O₃ with an admixture of tannic acid and Pt²⁺.This system can well respond to the acidic microenvironment of the tumor to strip Pt²⁺,which can be bound with DNA,preventing the replication and proliferation of tumor cells.The exposed iron oxide core can effectively promote the intracellular ferroptosis,thus curing the tumor.