Self-assembled Nanomaterials Based On Nitrogen-doped Graphene Quantum Dots And Sulfur Dioxide Gas Prodrugs For Sonodynamic/gas Combination Therapy Of Tumors

Nitrogen-doped graphene quantum dots（NGQDs）have good application prospects in the field of biomedicine due to their good biocompatibility,high stability,and unique properties.Recently,researchers found that NGQDs are three to five times more sonosensitizing than conventional sonosensitizers and can be used in sonodynamic therapy.Sonodynamic therapy（SDT）is a non-invasive cancer treatment method.Compared with traditional light therapy,SDT has good tissue penetration and can treat deep tumor tissues.However,the hypoxic tumor microenvironment and high concentrations of glutathione limit the efficacy of SDT.It is difficult to achieve ideal curative effect by relying on a single SDT.Gas therapy is an emerging green therapy.Gas molecules have good biomembrane permeability and can be transported into tumor tissue without any means,thereby inducing tumor cell apoptosis.However,due to the poor efficacy of single gas therapy,it is difficult to be used as a single treatment method,so gas therapy is often combined with other treatment methods to achieve better tumor treatment effects.In this paper,we prepared nitrogen-doped graphene quantum dots and sulfur dioxide gas prodrug sodium benzothiazole sulfinate（BTS）.In order to integrate the two into one and improve their accumulation in tumor tissue,the final material Gd-NGQDs/BTS@PLGA-PEG（GNBP）was obtained by self-assembly of NGQDs,BTS and Gd³⁺with block polymer PEG-PLGA by double emulsification-decompression solvent evaporation method.GNBP can realize MRI-guided sonodynamic/SO₂ gas combined therapy.The full thesis is divided into four chapters.In the first chapter,the preparation methods and applications of graphene quantum dots,the application of nitrogen-doped graphene quantum dots,the mechanism of sonodynamic therapy,the advantages of gas therapy,and the application of PEG-PLGA block polymers in tumor diagnosis and treatment are reviewed.Finally,the research idea of this thesis is put forward.In the second chapter,we introduce the preparation and characterization of GNBP self-assembled nanomaterials,explore the drug loading rate of BTS,and evaluate the magnetic resonance imaging ability,sonodynamic activity and SO₂ gas release performance of the material at the solution level.The material can be uniformly dispersed in water,has good magnetic resonance imaging performance,and can be used as a T₁-weighted magnetic resonance imaging contrast agent.The material has good SO₂ gas p H-responsive release ability,and shows excellent reactive oxygen species generation ability under the irradiation of ultrasound.In the third chapter,the therapeutic effect and biosafety of GNBP on cancer are explored at the cellular and in vivo levels.Cell-level experiments proved that the material has good biocompatibility.All indexes of mice after tail vein administration were normal.The above results indicate that GNBP has good biosafety.At the cellular level,GNBP caused greater damage to cells under ultrasound stimulation.At the in vivo level,the material was injected into mice through tail vein injection.GNBP was accumulated in the tumor sites on the left and right sides of the mouse through the EPR effect,and the material could release SO₂ gas in response to the tumor microenvironment.Under the action of ultrasound,GNBP produces a large amount of ROS at the tumor sites,which can kill the tumor tissue.In vivo treatment experiments showed that the tumor growth on the left and right sides of the mice was significantly inhibited.Due to the good tissue penetration of ultrasound,GNBP still had a good inhibitory effect on distal tumors.GNBP has good T₁-weighted magnetic resonance imaging performance at the in vivo level,and can be used as a T₁-weighted magnetic resonance imaging contrast agent to diagnose tumor sites,achieving integration of diagnosis and treatment.In the fourth chapter,the preparation,characterization and application of the related materials in this thesis and their application in tumor therapy are summarized.Finally,their further application in the field of tumor diagnosis and treatment is prospected.