Virus-like Mesoporous Silica For Nir-Ⅱ Fluorescence Imaging And Therapy Of Glioblastoma

Glioblastoma（GBM）is one of the most common malignant tumors in the brain due to its high mortality rate.Nowadays,chemotherapy combined with radiotherapy after operation is the main clinical treatment strategy.Because of the infiltrative growth of GBM,it is difficult to be completely resected and the recurrence rate is very high.Meanwhile,the presence of the blood-brain barrier（BBB）hampers drug delivery to the brain,drugs hardly reach effective therapeutic concentrations,resulting in poor therapeutic efficacy of GBM.To solve this problem,nano-drug delivery systems（NDDS）have designed to active target the BBB and GBM by modifying ligands,helping drugs cross the BBB and maintaining the necessary concentrations of drugs.Second near-infrared（NIR-Ⅱ）fluorescence imaging,a non-invasive imaging mode with high specificity and low side effects,has attracted much attention owing to deeper organizational penetration and higher resolution.Based on the above research background,we designed and synthesized virus-like mesoporous silica nanoparticles loaded with NIR-Ⅱ fluorescent probe IR-1061.Then,tannins（TA）,Fe³⁺,doxorubicin（DOX）and transferrin（Tf）were self-assembled to form TVSNP@1061/DOX.The TVSNP@1061/DOX nanoparticles could across the BBB and accumulate into GBM by Tf recognizing Tf receptors overexpressed on brain endothelial cells and GBM.Finally,we investigated the performance of TVSNP@1061/DOX for NIR-Ⅱ fluorescence imaging and antitumor therapy in vivo.The specific contents of this paper are as follows:Chapter 1.IntroductionThe chapter main introduced the application of metal polyphenol networks as surface modifiers,the current status of GBM therapy,the development and application of NIR-Ⅱ molecules and virus-like mesoporous silica.Finally,the purpose and significance of this thesis were analyzed.Chapter 2.Synthesis and characterization of TVSNP@1061/DOXIn this chapter,virus-like mesoporous silica nanoparticles were prepared,then TVSNP@1061/DOX nanoparticles were synthesized by further loading NIR-Ⅱ fluorescent probe IR-1061 and coating metal-polyphenolic networks containing DOX and Tf,which can cross BBB and target GBM.Meanwhile,a series of characterizations were carried out.TEM and DLS results showed that TVSNP@1061/DOX particle size was about 130 nm,dispersed well in PBS solution and had good stability in 10%FBS solution.The results of photothermal test showed that TVSNP@1061/DOX had good photothermal effect and photothermal stability.The release of DOX in vitro indicated that TVSNP@1061/DOX could achieve controlled DOX release in the presence of acidic lysosomes and glutathione（GSH）.To sum up,we have successfully constructed dual-targeting TVSNP@1061/DOX nanoparticles,which can be further used in cell and in vivo experiments.Chapter 3.TVSNP@1061/DOX antitumor research in vitroIn this chapter,we investigated the uptake rate of silica nanoparticles with different morphologies,the cytotoxicity and phototoxicity,and the ability to target BBB and GBM and the ability to produce ROS of TVSNP@1061/DOX.According to the experimental results,compared with solid and traditional mesoporous SiO₂,virus-like mesoporous SiO₂ showed better cellular uptake rate because of its unique shape.Meanwhile,Tf-modified TVSNP@1061/DOX can target BBB and GBM.The results showed that TVSNP@1061/DOX could also produce ROS at the cellular level,which indicated that TVSNP@1061/DOX had the potential for chemodynamic therapy.The results of cytotoxicity and phototoxicity experiments showed that TVSNP@1061/DOX exhibited strong photothermal toxicity under 1064 nm laser irradiation,which could be used to kill tumors.Chapter 4.Fluorescence imaging and antitumor research of TVSNP@1061/DOX in vivoThis chapter explored the fluorescence imaging ability and antitumor effect of TVSNP@1061/DOX in vivo.TVSNP@1061/DOX had a good ability to penetrate the BBB and target GBM in vivo.According to the experimental results of antitumor in mice,the tumor growth was obviously inhibited in TVSNP@1061/DOX+Laser group,suggesting combination photothermal therapy and chemotherapy showed excellent antitumor effect.In addition,the TVSNP@1061/DOX nanoparticles showed good biosafety by H&E staining sections of mouse organs and changes in mouse body weight.