Construcion And Application Of Near-infrared Light-responsive Multimodal Probes For Theranostics Of Glioma

Brain glioblastoma（GBM）is one of the most common and aggressive primary malignant brain tumors for adults.However,gliomas grow in an infiltrating manner,which rapidly invades the surrounding normal brain tissues.Thus,the current traditional treatment methods against gliomas show limitations.Cancer diagnosis and treatment based on nanotechnology has attracted extensive attention.However,the majority of nano-drugs with poor biocompatibility will be cleared by the body immune system,meanwhile the lack of active targeting on tumors decreases the treatment effect.Biofilms are introduced to coat multifunctional inorganic photothermal nanomaterials to solve the above issues due to the inherent advantages of long-term blood circulation ability of red blood cells,the homologous targeting ability of tumor cells and the inflammatory tendency ability of neutrophils.Triggered by the tumor microenvironment,a variety of tumor treatment modes are integrated into one nano-system to produce better treatment effects than a single mode.Based on this,this thesis designs three multi-modal biomimetic nanoprobes,which can accumulate in the tumor through intratumorally injection and active targeting for multi-modal collaborative diagnosis and treatment of glioma,providing new ideas and strategies for the integration of cancer diagnosis and treatment.In order to solve the shortcomings of the current nano diagnosis and treatment agents with only one single treatment mode,gold nano biconical/silver core-shell nanorods（Au/Ag NRs）are designed.The external surface camouflaged phospholipid membrane is introduced to improve their biocompatibility and realize the combined photothermal/chemokinetic treatment of tumors.Au/Ag NRs are prepared by overgrowth of anisotropic Ag on Au nano bionics,with uniform size,smooth surface and average length/width of 182.19±8.74/36.22±1.76 nm（aspect ratio of～5）.Au/Ag NRs show excellent photothermal performance with photothermal conversion efficiency（η）of 26.1%,which triggers the peroxidase-like（POD-like）activity under the tumor microenvironment and catalyzes the generation of hydroxyl radicals（·OH）from H₂O₂.Under the near-infrared light irradiation,PTT effect is produced to promote the generation of·OH.Moreover,CT imaging of this nanosystem can be realized.Therefore,Au/Ag NRs with multiple therapeutic modalities can realize the integration of diagnosis and treatment of tumor photothermal/chemical dynamics.Due to the weak tumor tendency of synthetic phospholipid membrane,the indocyanine green（ICG）-doped mesoporous silica nanoparticles（MSNs/ICG）coated with red blood cell membrane modified by targeting polypeptide cRGD（fC）are fabricated.The mesoporous structures are used to load gene drug（miR-137）to construct a nano diagnostic probe（MSNs/ICG/miR/RM/RGD）with photothermal/gene combination therapy.The camouflaged red blood cell membrane（RM）on the surface extends its circulation time in vivo and promotes the immune escape.cRGD（fC）polypeptide on the surface of red blood cell membrane functions as a target molecule to achieve efficient tumor accumulation.Under the irradiation of near-infrared light,the nanoprobe can rapidly increase the temperature of the tumor and promote the rapid release of miR-137.The in vivo experimental results show that the effect of inhibiting subcutaneous glioma is as high as 94.9%.Meanwhile,it can perform near-infrared fluorescence and photoacoustic（PA）dual-mode imaging.Therefore,the developed nanoprobe can be used as a carrier for targeted delivery of gene drugs and realize photothermal/gene synergistic therapy and multi-mode imaging of subcutaneous tumors.In order to further improve the tumor targeting effect,a nanozyme（GOx/HPB/NEM）with cascade enzymatic reaction is constructed by using the endogenous neutrophil membrane to camouflage the hollow Prussian blue nanoparticles（HPB）loaded with glucose oxidase,which is used for photothermal/starvation synergistic therapy and photoacoustic（PA）imaging of glioma.Prussian blue nanoparticles are prepared by an improved hydrothermal method,and the hollow structure is obtained by high acid etching.The results of TEM,XRD,BET and XPS show that HPB was successfully prepared.After being coated with neutrophil membrane,GOx/HPB can be effectively delivered to tumor cells.After near-infrared irradiation,GOx is rapidly released in tumor cells,and a large amount of glucose in tumor cells is consumed to produce gluconic acid and H₂O₂.The generated H₂O₂ is subsequently catalyzed by hollow Prussian blue with peroxidase activity（CAT）to produce O₂,which alleviates the hypoxia of tumor microenvironment,improves the catalytic efficiency of GOx and improves the starvation treatment effect.Sufficient starvation of tumor cells leads to ATP deficiency,thus inhibiting the upregulation of HSP70 and reducing the heat tolerance of tumor cells.In vivo and in vitro experiments have proved that the cascade enzymatic reaction of the nanozymes enhances the synergistic effect of photothermal/starvation treatment against tumors.The tumor growth inhibition rate reaches 97.7%.Therefore,this biomimetic nanoprobe provides a potential solution for the integration of tumor diagnosis and treatment in the future.