Phosphorus-based Nanoprobe For Regulation Of Tumor Microenvironment

Tumor microenvironment is a complex environment for tumor cells to survive,and it is closely related to the occurrence,development,invasion and metastasis of tumors.The tumor microenvironment has a series of physical and chemical properties that are different from normal microenvironment,such as weak acidity,hypoxia,and redox imbalance.The abnormal physical and chemical properties of the tumor microenvironment are not only considered to be side effects caused by tumor growth,but also considered to be key factors affecting tumor progression.Regulating the physical and chemical parameters of the tumor microenvironment is expected to affect the progress of the tumor and improve the tumor’s response to therapy,ultimately achieving the inhibition of tumor growth.With the advantages of small size,easy to design,and multifunctional integration,nanoprobes play an important role in the regulation of tumor microenvironment,such as regulating p H,alleviating hypoxia and improving reactive oxygen species.However,these nanoprobes still face some challenges for the tumor microenvironment response and regulation.For example,nanoprobes usually contain inorganic elements that do not exist in the organism,and their biological safety remains to be studied.In the tumor microenvironment,tumorrelated cells and their secreted cytokines and chemokines promote tumor metastasis.Nanoprobes need to simultaneously regulate the molecules and cells in the tumor microenvironment after regulating the physiological parameters of the tumor microenvironment.Therefore,it is very necessary to design biocompatible and multifunctional nanoprobes for regulating the tumor microenvironment.Phosphorus-based functional materials are nanomaterials including phosphorus element,which have the characteristics of high biocompatibility and low immune rejection.These features effectively reduce the side effects of phosphorus-based functional materials on normal tissues,while provide the possibility for phosphorusbased functional materials to regulate molecules and cells in the body.At present,the representative phosphorus-based functional materials are black phosphorus nanomaterials and calcium phosphate nanomaterials.The properties of black phosphorus nanomaterials including p H response,wideband optical response and high specific surface area make them show great potential in the construction of multifunctional phosphorus-based nanoprobes.Calcium phosphate nanomaterials have the characteristics of p H response,biodegradability and biocompatibility.In an acidic microenvironment,calcium phosphate nanomaterials can be degraded into non-toxic phosphate.The phosphate can not only regulate the enzyme activity in the tumor microenvironment,but also can change the metabolism of tumor cells via enzyme activity.With the rapid development of nanotechnology research,phosphorus-based functional materials are being used to design nanoprobes with a variety of special functions and properties,broadening the application prospects for the analysis and regulation in the complex tumor microenvironment.In this work,we focus on the biocompatibility and versatility of nanoprobes in the complex tumor microenvironment for the field of disease diagnosis and treatment.Based on phosphorus-based nanomaterials,a variety of phosphorus-based nanoprobes with tumor microenvironment response have been designed and prepared.We further explored the effects of phosphorus-based nanoprobes on redox balance,tumor metabolites and tumor growth.The main contents of this dissertation are as follows:(1)In the tumor microenvironment,the destruction of the intracellular redox balance will produce a large amount of reactive oxygen species,eventually leading to tumor cell apoptosis.Under light irradiation,black phosphorous nanomaterial can react with oxygen to generate reactive oxygen species,such as superoxide radicals,singlet oxygen.We encapsulated the up-conversion nanoparticles @ black phosphorus quantum dots in phospholipid bilayer modified by aptamer to construct phosphorusbased liposome with the regulation of redox homeostasis.The phosphorus-based liposome under near-infrared light irradiation can effectively generate singlet oxygen,and subsequently realize the regulation of redox in tumor cells.In addition,the phosphorus-based liposome has a strong anti-tumor effect and effectively inhibits the growth of tumor tissues.The phosphorus-based liposome not only provides a method for the design of near-infrared light-responsive phosphorus-based nanoprobes,but also provides a way for phosphorus-based nanoprobes in the regulation of tumor microenvironment.(2)In hypoxic tumor microenvironment,long-term accumulation of adenosine in tumor tissues helps to establish the immunosuppressive tumor microenvironment and to promote tumor development.We constructed phosphorus-based frameworks to restore the activity of adenosine kinase and to promote adenosine phosphorylation in hypoxic cells.In the acidic condition,calcium phosphate coated on phosphorus-based frameworks are degraded to produce phosphate,restoring the adenosine kinase activity.Subsequently,these phenomena will promote adenosine phosphorylation catalyzed by adenosine kinase.Metal moieties in phosphorus-based frameworks can undergo Fenton-like reaction and produce oxygen,improving the hypoxia in tumor cells.In addition,the generated oxygen inhibits the production of adenosine by inhibiting the expression of adenosine production-related proteins,finally achieving decrease of adenosine.The phosphorus-based frameworks not only provide new insight for the regulation of adenosine metabolism in the tumor microenvironment,but also provide new direction for the study of adenosine-mediated immunosuppression.(3)Tumor is a metabolic disease,and metabolites are the key components involved in tumor metabolism.Changes of physiological parameters in the tumor microenvironment affect the metabolic processes of tumor-related cells,leading to changes of metabolites in the tumor microenvironment.The phosphate transfer reaction mediated by adenosine kinase can catalyze the phosphorylation of adenosine to adenosine monophosphate,changing the level of various metabolites in the tumor microenvironment.We constructed a phosphorus-based cell membrane that can be degraded under acidic conditions or in tumor cells,and we further used the phosphorusbased cell membrane to regulate the phosphate transfer reaction catalyzed by adenosine kinase.In tumor cells,the phosphorous-based cell membrane changes the ratio of four nucleotide metabolites,inducing the occurrence of autophagy.The phosphate transfer reaction promoted by the phosphorus-based cell membrane successfully regulates the process of nucleotide metabolism in tumor cells,which is expected to provide a broad prospect for regulating tumor metabolism and inhibiting tumor development.