Functional Modification Of Gd And Mn Doped Hollow Silica Spheres And Its Application In Tumor Diagnosis And Treatment

Hollow silica nanospheres have the advantages of large internal cavity,high specific surface area,high stability and dispersion.Their empty cavity can accommodate a large number of guest molecules and can be used for drug delivery,gene delivery,biological imaging,and cancer therapy.Hollow silica nanospheres are highly biocompatible,safe and non-toxic,and are widely used in the biomedical field.Sonodynamic therapy（SDT）is a promising new method for cancer treatment that uses low-intensity ultrasound and chemicals（called sonosensitizers）to produce reactive oxygen species（ROS）that can cause toxic effects on cancer cells.Compared to the limited penetration of near-infrared light in photodynamic therapy,ultrasound is a mechanical wave that can penetrate deep into tumor tissue and can easily act on deep tumor cells.In addition,ultrasound can accurately focus on the tumor site,enabling sonodynamic therapy to accurately kill tumor cells with minimal dose and minimize damage to surrounding normal tissue.Curcumin is a kind of sonosensitizers and it has antitumor pharmacological activity.The sonosensitizer can be accumulated in the tumor site by the enhanced permeability and retention effect（EPR）with the nanomaterial as a carrier,and the therapeutic effect is remarkably enhanced without changing the structure and properties of sonosensitizer.NO gas therapy can overcome the resistance of sonodynamic therapy in the absence of oxygen and enhance the effect of sonodynamic therapy.In addition,NO gas itself can also induce tumor cell apoptosis.In this thesis,we synthesized metal-doped hollow silica nanospheres and functionalized them to obtain nanocomposites with ultrasound/magnetic resonance dual-mode imaging to guide tumor combined therapy.And the imaging and tumor treatment effects of the prepared nanocomposites were studied.The full text is divided into four chapters.The first chapter summarizes the mechanism of sonodynamic therapy and the types of sonosensitizer,as well as the role and types of gas therapy,and puts forward the research ideas.In the second chapter,we prepared and characterized Cur@Gd-HSN-CMD nanocomposites.The drug loading of curcumin,ultrasound imaging and magnetic resonance imaging performance,and the effect of chemotherapy/sonodynamic therapy were studied.The prepared Gd-HSNs exhibited a hollow spherical appearance with uniform particle size.The in vitro cell MTT assay and hemolysis experiments showed that Gd-HSN-CMD material has low cytotoxicity and good biocompatibility.Due to the cavity structure of the material and the doping of Gd³⁺,the material has the properties of ultrasonic imaging and magnetic resonance imaging in vitro and in vivo,and can be used as an ultrasound/magnetic resonance dual-mode imaging contrast agent.Curcumin,which was loaded in Gd-HSN-CMD material,produced reactive oxygen species（ROS）under ultrasound excitation.Combined with the chemotherapeutic effect of curcumin itself,Cur@Gd-HSN-CMD material produced high toxicity on 4T1 cells.After injection of Cur@Gd-HSN-CMD into the tail vein of tumor-bearing mice,the material can effectively accumulate in the tumor site through the EPR effect.After treatment,the tumor growth of the mice was greatly inhibited,indicating that the material has a good cancer chemotherapy/sonodynamic therapy effect.In vivo blood and histopathological analysis showed that the main organs and blood indexes of the mice were within the normal range,indicating that the combination therapy with Cur@Gd-HSN-CMD did not produce obvious side effects.In the third chapter,Mn-doped hollow mesoporous silica nanospheres（Mn-HMSNs）were prepared,and modified with the NO donor S-nitrosothiol（R-SNO）by introduction of sulfhydryl groups.PEG was grafted on the surface of Mn-HMSNs to improve their biocompatibility,and finally the sonosensitizer Rose Bengal（RB）was loaded in the cavity of the nanospheres to obtain RB@Mn-HMSN-SNO/PEG nanocomposites.The morphology of the synthesized Mn-HMSNs is a hollow sphere composed of many small vesicles with uniform size.Mn-HMSN-PEG exhibits good magnetic resonance imaging contrast performance due to the doping of Mn element.Under ultrasound excitation,Rose Bengal in RB@Mn-HMSN-SNO/PEG is activated to produce ROS,and the ROS induces the cleavage of S-N bonds in-SNO to release NO gas,thus exhibiting excellent gas/sonodynamic therapy effect at the cellular level.The fourth chapter summarizes the experimental data and results in this thesis,including the preparation,characterization and biomedical application of the materials.Finally,the future application research is prospected.