Application Of Multifunctional Dendritic Mesoporous Silicon-based Nanocomposite In Tumor Optical Diagnosis And Therapy System

Phototherapy,which mainly including photothermal therapy（PTT）and photodynamic therapy（PDT）,has been widely concerned as an effective therapeutic measure with minimal side effects for cancer therapy over the past decades.Induced by photothermal agents,PTT can transform excited light source to heat through the nonradiative relaxation of excited electrons,leading the necrosis of cancer cells because of the increased temperature.PDT converts oxygen to cytotoxic singlet oxygen by photosensitizer under light irradiation,leading to apoptosis of tumor cells.Tumor tissue has its special microenvironment,such as weak acid,hypoxia,hydrogen peroxide and glutathione overexpression.Although these factors may limit the therapeutic effect,they can also serve as driving forces to improve the therapeutic effect of stimulus-responsive nanocomposites.Therefore,it is of great significance to design multifunctional nanocomposites for the combined diagnosis and therapy systems including phototherapy,with near-infrared light source as the exogenous stimulus and the response ability of nanocomposites in tumor microenvironment as the driver for the promotion of tumor clinical therapy.The specific contents of this thesis are as follows:In order to solve the problems of trauma,poor selectivity and drug resistance in the traditional tumor treatments,tetrasulfide bond combined dendritic mesoporous organosilica nanoparticles（DMOS）were used as nanocarriers for chloroperoxidase delivery and then coated with sodium hyaluronate modified calcium peroxide nanoparticles to establish a non-photoexcited dynamic therapy system,enzyme dynamic therapy（EDT）.DMOS nanoparticles can be degraded rapidly in response to glutathione and used as a new source of hydrogen sulfide.Due to the depletion of glutathione,the compensation of hydrogen peroxide,and the mitochondrial damage caused by hydrogen sulfide,the effect of EDT was greatly enhanced.The apoptosis rate of tumor cells was up to 92%.At the same time,the nanocomposite can cause tumor cell calcification.In vivo experiments fully demonstrated that the synthesized nanocomposite could effectively inhibit tumor growth,and the tumor inhibition rate was 94%.The survival time of the treated mice was more than 40 days.Therefore,exploring a non-photoexcited EDT can improve the further application of nanocomposite in cancer therapy.To solve the problems of obtaining,expensive and difficult storage of chlorperoxidase in EDT system,modified dendritic mesoporous silicon nanoparticles were used as carriers to carry indocyanine green to construct an efficient and low-cost optical diagnosis and therapy system.Inert dendritic mesoporous silicon nanoparticles were etched by Mn²⁺in alkaline environment to obtain activated dendritic mesoporous manganese silicate nanoparticles loaded with indocyanine green and glucose oxidase.By establishing a catalytic cascade process between Mn²⁺and glucose oxidase,glucose in tumor cells is consumed in large quantities,achieving the goal of starvation therapy.At the same time,the improvement of hypoxia and glutathione consumption greatly improved the photodynamic therapy effect of indocyanine green.In addition,indocyanine green also showed good photothermal therapy performance,and the photothermal conversion efficiency was 23.8%.Due to the combined therapeutic effect of starvation therapy and phototherapy,the nanocomposite can effectively inhibit tumor growth,and the tumor inhibition rate is 86%.Therefore,this study successfully constructed a unique and efficient optical nanosystem based on catalytic cascade for anti-tumor diagnosis and therapy.In order to solve the problems of low encapsulation rate and reduced enzyme activity of glucose oxidase in the above study,calcium phosphate was grown on the surface in situ.Thus,the dendritic mesoporous manganese silicon nanoparticles loaded with indocyanine green were calcified.The synthesized nanocomposite decomposed rapidly in response to weak acidity and glutathione,releasing Mn²⁺,Ca²⁺and indocyanine green.Due to effective glutathione depletion and multiple oxygen compensation,the nanocomposite exhibited a significantly improved phototherapeutic effect with a tumor suppression rate of 78%.The designs of this simple and effective calcified nanocomposite will provide a new idea for improving the application of phototherapy in the field of cancer treatment.Metal ion etching by hydrothermal synthesis method in the above two studies can not ensure the uniformity of the process,and the etching degree of the obtained products can not keep the same.In order to solve the above problems,Mn²⁺,Fe³⁺or Co²⁺and tetrasulfide bonds were combined into dendritic mesoporous organosilicon nanoparticles through the strong interaction between sulfonic acid groups and metal ions in the template.Three kinds of nanoparticles were obtained:Mn-DMOS nanoparticles,Fe-DMOS nanoparticles and Co-DMOS nanoparticles.Due to the joint binding of the metal ions and the tetrasulfide bonds,these designed nanoparticles exhibited more functionality than only used as nanocarriers.Mn-DMOS nanoparticles were used as carriers to carry indocyanine green and then modified with DSPE-PEG.The photothermal conversion efficiency of the nanocomposite was 19%.The phototherapeutic efficiency of the nanocomposite was significantly improved due to glutathione depletion and trimodal oxygen compensation,with a 75%tumor suppression rate.Simple and effective design and synthesis of dendritic mesoporous organosilicon nanoparticles co-bound with metal ions and tetrasulfide bonds will play an important role in the development and application of multifunctional nanocapsules in the field of tumor phototherapy.