Tumor Microenvironment-responsive Functional Materials For Efficient Tumor Diagnosis And Treatment

The tumor microenvironment is closely related to the development of tumors.The complex tumor microenvironment not only promotes tumor growth and metastasis,but also makes tumors highly resistant to multiple therapeutic techniques.Therefore,this thesis focuses on the tumor microenvironment and designs tumor microenvironment-responsive nanomaterials,utilizing the characteristics of high levels of glutathione（GSH）,polyamines,and hypoxia in the tumor microenvironment.High-efficiency tumor diagnosis and treatment have been achieved from the following three aspects:monitoring tumor microenvironment,utilizing tumor microenvironment,and regulating tumor microenvironment.The main research contents are as follows:1.Magnetic resonance energy transfer strategy（MRET）based on susceptibility weighted imaging（SWI）for precise monitoring of GSH in tumor areas.At present,the reported GSH-responsive MRI nanoprobes still have several disadvantages,such as low sensitivity and inability to accurately detect GSH in living tumors.Based on this,we proposed an innovative SWI-based MRET strategy with thedesign and synthesis of a GSH-responsive nanoprobe（Fe₃O₄-SS-Co Fe₂O₄）.After reaching the tumor site,the nanoprobe can respond sensitively to excessive GSH in the tumor microenvironment.GSH decreases the magnetic susceptibility of the material and the change of SWI signal,thereby achieving accurate detection of the GSH content in living tumors.In short,this strategy not only improves the detection sensitivity of GSH-responsive MRI probes,but also provides new ideas for the design of MRI nanoprobes used for monitoring other microenvironment of tumor.2.Utilizing polyamines in the tumor microenvironment to achieve carbonyl stress strategy for oxidative damage treatment of tumor.The high levels of polyamines in the tumor microenvironment can promote the growth of tumor cells and severely inhibit lipid peroxidation（LPO）and DNA damage caused by free radicals,resulting in the low efficiency of tumor treatment.Based on this,we propose a carbonyl stress strategy activated by polyamines in the tumor microenvironment to effectively overcomes the inefficient oxidative damage treatment,which can convert high levels of polyamines in the tumor microenvironment into toxic hydrogen peroxide（H₂O₂）and acrolein.By loading polyamine oxidase（PAO）into MIL-100with high Fenton reaction activity,and further modifying it with polyvinylpyrrolidone（PVP）,the MPP（MIL-100@PAO@PVP）nanoparticles with good dispersibility was obtained.After MPP nanoparticles reach the tumor site,they will quickly consume the polyamine in the tumor site and produce a large amount of hydrogen peroxide（H₂O₂）and acrolein.Among them,H₂O₂promotes the oxidative damage induced by Chemodynamic Therapy（CDT）.More importantly,the highly toxic acrolein can further trigger carbonyl stress and inhibit the function of glutathione peroxidase 4（GPx4）and DNA repair protein,thereby exacerbating cell apoptosis induced by oxidative damage.The polyamine-activated carbonyl stress strategy proposed in this study can not only promisingly overcome the low efficiency of oxidative damage,but also provide new ideas for utilizing tumor microenvironment to achieve high-efficiency tumor treatment strategies.3.Utilizing magnesium silicide nanoparticles to regulate the tumor microenvironment for radiotherapy sensitization research.In radiotherapy,the amount of hydroxyl radicals（·OH）and the pre-hydration electrons produced by X-ray-induced water splitting are equal,and the DNA damage efficiency of the pre-hydration electrons is twice that of·OH.However,a large number of prehydrated electrons will be quickly quenched by oxidizing species（O₂,H₂O₂,·OH,etc.）in the tumor microenvironment,which severely limits the efficacy of radiotherapy.Based on this,we proposed a reductive regulation strategy of tumor microenvironment mediated by magnesium silicide nanoparticles to enhance the radio-sensitization effect of pre-hydrated electrons.Among them,the reducing silane released by magnesium silicide nanoparticles respond to the acidic tumor microenvironment can effectively remove oxidative species in the tumor microenvironment,significantly increase the number of pre-hydrated electrons during tumor radiotherapy,and enhance the therapeutic effect.Both in vivo and in vitro experimental results show that magnesium silicide nanoparticles have a promising tumor radio-sensitization effect,and the reducing microenvironment induced by magnesium silicide nanoparticles effectively inhibits the expression of DNA repair proteins.This tumor microenvironment regulation strategy not only effectively improves the efficacy of radiotherapy,but also provides new ideas for the study of radiotherapy sensitization.