Preparation Of The Biodegradable Mesoporous Organosilica Nanosheets And Their Applications For Cancer Therapy

In recent years,cancer has become one of the most fatal diseases.Traditional treatment methods include chemotherapy,radiotherapy and surgical resection.However,these methods often bring great side effects and unsatisfactory treatment effect.With the rapid development of nanobiotechnology,cancer treatment also has more diverse and more selective treatment methods.Considering the unique advantages of nanomaterials in drug delivery,diagnosis（imaging,therapeutic agents）and targeted therapy,more and more versatile nanomaterials have been developed to serve as a loading platform for chemotherapeutic drugs to achieve the treatment of tumors.Among the numerous nanocarriers,silica-based nanomaterials have received extensive attention due to their good biocompatibility,adjustable structural features and modifiable surface chemical properties.However,due to its unique SP³ atomic orbital hybridization method,silica nanoparticles are prone to appear in non-planar form.And there are very few reports on silica nanosheets,especially in biological diagnosis and treatment applications.Compared with traditional silica nanoparticles,biodegradable mesoporous organosilica nanosheets with atomic thickness have a larger specific surface area,meaning that they can carry more chemotherapy drugs.Moreover,its sheet-like morphological characteristics will also affect the uptake capacity of cells and the degradability of the material itself.Therefore,we have used chemotherapeutic drugs and the easily modified surface features to successfully develop a nano-medicine platform that integrates chemotherapy and hyperthermia or chemotherapy and chemodynamic therapy.The specific research content is as follows:1.Preparation and performance evaluation of biodegradable mesoporous organosilica nanosheets.In this chapter,starting from the larger silica nanosheets,a variety of methods are used to try to reduce the size.Specific methods include lowering the temperature,changing the p H,reducing the concentration of the reactants,replacing the reactants,shortening the reaction time and ultrasonic treatment.Then using CTAB as a template and BTES/TEOS as a silicon source to successfully obtain biodegradable mesoporous organosilica nanosheets.The load capacity of the cargo and the drug release at different glutathione（GSH）concentrations were tested.And the degradation at different GSH concentrations was also performed.Finally,the cell phagocytosis of the material and the toxicity of the material itself were initially tested through cytotoxicity experiment.The conclusions are as follows:（1）The methods of lowering temperature,changing p H,reducing reactant concentration,replacing reactants and shortening reaction time have little effect on the size of silica nanosheets.Only under high-intensity ultrasound can reduced the size of silica nanosheets.（2）Through the simulated loading of FITC,the biodegradable mesoporous organosilica nanosheets showed excellent cargo loading capacity and the characteristics of response release to GSH.（3）Compared with traditional tetrasulfide bond-doped organic silica nanoparticles,our organosilica nanosheets show better degradation performance.（4）The cytotoxicity experiments verify that our materials have good biocompatibility.And cell uptake experiments show that cells have good uptake properties for the materials.In summary,we have successfully prepared degradable mesoporous organosilica nanosheets.And the mesoporous organosilica nanosheets have excellent degradability.2.Construction of CuS@NSs-DOX integrating mild hyperthermia and chemotherapy and its performance evaluation in tumor treatment.On the basis of the second chapter,using small pieces of mesoporous organosilica nanosheets as a template,the copper sulfide nanoparticles with photothermal effect were successfully bonded to the surface with thiol bond to obtain CuS@NSs.Then,by using the porous characteristics of CuS@NSs,the chemotherapeutic drug DOX was successfully loaded.After considering the degradation performance of CuS@NSs,we simulated the effects of temperature,p H value and GSH on the release of chemotherapeutic drug DOX in vitro.Next,the cell experiment was used to further test the toxicity of CuS@NSs+DOX to the cells and the uptake by the cells.Finally,through experiments in vivo,the treatment of tumors and side effects on the body were determined.The conclusions are as follows:（1）CuS@NSs has a high drug load which the DOX load is up to 859μg/g.（2）The release of the chemotherapeutic drug DOX is subject to a triple intelligent response of temperature,p H,and GSH concentration.（3）The photothermal effect of CuS@NSs is affected by its concentration and the intensity of the near-infrared laser.By controlling the concentration of CuS@NSs and the intensity of the laser,the temperature can be maintained within 41-43 ⁰C to achieve mild thermotherapy.（4）Combined with confocal microscope photos,we can found that the CuS@NSs are more easily uptaken by cells compared with traditional spherical silica nanoparticles,while mild hyperthermia will further promote cell uptaken.In addition,the vitro cell experiments and the vivo experiments indicate that the combination of chemotherapy and photothermal therapy has a good anti-tumor effect.3.Construction of Fe MOFs@oSiO₂ NSs-DOX integrating chemical kinetic therapy and chemotherapy and performance evaluation in tumor treatment.In this chapter,we continue to use small pieces of degradable organosilica nanosheets（sSiO₂ NSs）as a template to successfully grow Fe MOFs materials on sSiO₂ NSs by layer-by-layer growth.Through the porosity of the MOFs material,the chemotherapeutic drug DOX was successfully loaded.And we test the drug release of Fe MOFs@oSiO₂ NSs-DOX at different p H values and the generation of reactive oxygen species（ROS）under different conditions.After that,we determined the toxicity of Fe MOFs@oSiO₂ NSs-DOX and the generation of ROS in cells through cell experiments.Finally,we preliminary explored the distribution of Fe MOFs@oSiO₂ NSs-DOX in vivo through in vivo experiments.The conclusions are as follows:（1）Fe MOFs@oSiO₂ NSs show excellent drug loading capacity.（2）Fe MOFs@oSiO₂ NSs-DOX drug release is controlled by p H value intelligently.（3）Fe MOFs@oSiO₂ NSs-DOX showed excellent ROS generation ability in vitro simulation test.（4）Cell experiments showed that Fe MOFs@oSiO₂ NSs-DOX has strong cytotoxicity.The toxicity is resulting from the generation of ROS and chemotherapy drugs.And the distribution experiment in vivo also showed that Fe MOFs@oSiO₂ NSs-DOX can well gather at the tumor site.