Functionalized Modification Of Rare Earth Metal Doped Hollow Silica And Its Application In Tumor Diagnosis And Treatment

Hollow-structured mesoporous silica materials that consist of a large internal cavity within a mesoporous shell have attracted increasing attention across various fields.Especially,silica-based hollow mesoporous nano/micro-spheres,are regarded as one of the most clinically promising nanomaterials for biomedical applications,owing to their large internal cavity structure,high surface area,favorable biocompatibility,and facile surface modification.It is often used as a drug carrier because of its internal cavity which can accommodate a large number of guest molecules.Tirapazamine(TPZ)is a bioreductive prodrug with high selective toxicity to hypoxic cancer cells.Hollow mesoporous silica nanospheres can load TPZ into its cavity.Due to the prevalence of hypoxia in malignant solid tumors,the sensitivity of tumors to radiotherapy and chemotherapy decreases and results in tumor angiogenesis and tumor cell metastasis.Bioreductive drugs can specifically act on tumor hypoxic tissues which are reduced to cytotoxic metabolites by enzymatic reactions.Sonodynamic therapy is very suitable for the treatment of tumors in deep tissues because of the strong tissue penetration of ultrasound.The combination of bioreductive therapy and sonodynamic therapy can induce synergistic therapy,because the oxygen consumption during the process of sonodynamic therapy activates hypoxic prodrugs.Thus,the oxygen-rich and hypoxic regions of tumor tissues can be treated efficiently,reducing the possibility of tumor metastasis and recurrence.In this paper,we synthesized rare-earth-doped hollow mesoporous silica nanospheres and further functionalized the surface of the nanospheres.Then,we evaluated the biocompatibility of the prepared nanocomposites and the therapeutic effects on tumors.Besides,we found that both prepared nanocomposites were multifunctional.They both could be applied in ultrasound and T2-weighted magnetic resonance imaging.The dissertation is divided into four chapters.In the first chapter,we summarize the mechanism of sonodynamic treatment and its application in tumor therapy,the applications of the sonosensitizer chlorin e6 in sonodynamic therapy,and the biological application of bioreductive drug tirapazamine.In the second chapter,the Ho-HSN-Ce6/PEG-mAbPSCA multifunctional nanomaterial was prepared and characterized.We also studied its drug loading capacity and release behavior to the tirapazamine(TPZ),the in vitro and vivo cancer therapy and the ultrasound/magnetic resonance dual-mode imaging function.The synthesized Ho-HSNs was in good morphology and small size.The prepared Ho-HSN-Ce6/PEG-mAbPSCA held good solubility and can be stably dispersed in several physiological solutions.The in vitro MTT experiments demonstrated that the Ho-HSN-Ce6/PEG-mAbPSCA had low cytotoxicity and low hemolytic activity.The material has high echo properties and paramagnetic properties of Holmium and it can be used as a targeted ultrasound/magnetic resonance dual-mode imaging contrast agent for monitoring tumor sites.Ho-HSN-Ce6/PEG-mAbPSCA has a high loading capacity for bioreductive drug TPZ.It has a low drug leakage under normal physiological conditions and the drug can be released rapidly when it is in the tumor microenvironment.The conjugated Ce6 in TPZ@Ho-HSN-Ce6/PEG-mAbPSCA can generate reactive oxygen species(ROS)under US irradiation for killing the cancer.Then,the hypoxic microenvironment was created due to oxygen consumption induced by SDT,which then activated TPZ for hypoxia-specific killing effect and potentiated the anticancer efficacy to a large extent.In the third chapter,we firstly prepared and characterized gadolinium-doped hollow silica nanospheres(Gd-HSNs).Then,the surface of Gd-HSNs was modified with silicon dihydroxylphthalocyanine(SPCD)and mPEG-Silane to produce the multifunctional Gd-HSN-SPCD/PEG nanomaterials.Gd-HSNs were prepared by hydrothermal method.SPCD and mPEG-Silane were modified on the silica surface by hydrolysis of Si-OH or silane.The as-prepared Gd-HSN-SPCD/PEG showed uniform hollow spherical morphology and good dispersibility in aqueous solutions.The results of the synergistic therapy and AM/PI double staining experiments using 4T1 cells showed that the Gd-HSN-SPCD/PEG material had good phototherapeutic effect.Gd3+has 7 non-paired electrons,high spin magnetic moment,electric field symmetry,and high relaxation rate.Meanwhile,the hollow nanospheres have excellent echogenic property.Therefore,HS-Gd-SPCD/PEG showed good contrast effect in MR and US imaging.Gd-HSN-SPCD/PEG is expected to combine MR,US imaging and cancer photothermal/photodynamic therapy into one system,and such nanomaterials have good application prospect in the field of biomedicine.In the fourth chapter,we summarize the obtained experimental data and results about the preparation,characterization and the biomedical applications of the prepared multifunctional nanocomposites,and finally make an outlook about its further application in the future.