Construction And Evaluation Of Mesoporous Organosilica Based Drug Delivery Systems And Their Antitumor Therapy

Nowadays,the specific diagnose and treatment of tumor is still a hot and difficult topic in life scientific research.With the rapid development of nanotechnology,nanomedicine has been widely applied in the field of tumor theranostic and safe medication,which provides an innovative strategy to possibly overcome tumor.Mesoporous silica nanomaterials have many advantages,such as large specific surface area,uniform and adjustable pore size and easy functionalization,exhibiting attractive application prospects in nanomedical fields of drug delivery and tissue engineering.However,the defects of pure inorganic silicon skeletons lie in their difficult degradation and poor response of drug release in the tumor microenvironment,which limit their further application in the biomedical field.Therefore,it is of great significance to design silicon-based nanocarriers with biodegradable property and better drug response performance to tumor microenvironment.Based on the demands discussed above,this dissertation started with the synthesis of mesoporous organosilica nanoparticles（MONs）with controllable morphology and biodegradable skeleton.The MONs were endowed with stimuliresponsive ability to the tumor microenvironment,and their antitumor activities were evaluated both in vitro and in vivo.The contents of this thesis included two aspects,which are summarized as follows.Ⅰ.Construction and evaluation of interface engineered Paclitaxel/IR820@HMONs-PEG drug delivery system and its photothermal-enhanced chemotherapy of tumor.Paclitaxel,as a traditional chemotherapeutic agent,has been widely used in the clinical practice,but its efficiency is largely limited due to the inherent poor solubility,systemic side effects and susceptibility to multidrug resistance.Therefore,researchers have developed many paclitaxel-loaded nanodrug delivery systems,but there still remains some problems such as unsatisfying loading efficiency,unpredictable drug leakage and poor response of drug release when exposed to the tumor microenvironment.Considering that mono-chemotherapy is often difficult to achieve the ideal therapeutic effect,the combination of chemo-photothermal therapy can effectively promote the intracellular uptake of the drugs,and achieve photothermal ablation to jointly eliminate tumor cells,which can effectively improve the antitumor efficiency.Based on these background,biodegradable organic/inorganic hybrid hollow mesoporous organosilica nanoparticles（HMONs）were prepared by the principle of "chemical homology".The HMONs were utilized to simultaneously encapsulate the chemotherapeutic drug paclitaxel and the photothermal conversion agent IR820,and polyethylene glycol was further utilized to improve its biocompatibility to obtain a paclitaxel and IR820 co-loaded drug delivery system（denoted as Paclitaxel/IR820@HMONs-PEG）for photothermal enhanced chemotherapy of tumor.The results showed that the prepared Paclitaxel/IR820@HMONs-PEG had high drug loading efficiency of paclitaxel（28.4 %）with high efficiency and stability,better than most paclitaxel-based nanocarriers reported in the literature.Dynamic light scattering instrument,transmission electron microscopy,specific surface area analyzer and flourier infrared spectrometer were applied to verify its appearance and structural composition.Glutathione responsive drug release analysis,in vitro photothermal conversion studies and hemolysis experiments confirmed that the drug delivery system had great GSHresponsive drug release behavior,good photothermal conversion performance and great biocompatibility.In vitro cellular uptake,cytotoxic assay,live and dead cell staining experiments and cell apoptosis studies verified its effectively synergistic antitumor effect.Besides,in vivo tumor inhibition experiments further confirmed that the nanodrug delivery system had superior tumor regression ability.Ⅱ.Construction and evaluation of functionalized Aloe-emodin/IR820@PMONsPEG drug delivery system and its combinational chemo-photothermal antitumor therapy.Aloe-emodin is one of the main components of the traditional Chinese medicine rhubarb in Gansu Province,which can effectively exert antitumor effects through multiple mechanisms.However,its poor water solubility,obvious first-pass effects and low bioavailability limit its druggability.In this study,the hydrophilicity and hydrophobicity of the mesoporous silicon framework could be easily adjusted by changing the types and properties of those organic groups doped in the framework,which helps to effectively encapsulate the aloe-emodin through hydrophobic interactions between molecules,and thus improves its druggability and tumor-targeted drug delivery capability.Meanwhile,to further improve the GSH-responsive drug release behavior,PMONs with both disulfide and tetrasulfide bonds were synthesized.And the improved treatment efficacy could be achieved by promoting effective drug encapsulation via hydrophobic force and the specific drug release of the tumor site.On the other hand,due to the inherent defects of mono-chemotherapy,the photothermal conversion agent IR820 was further encapsulated into the nanocarriers to achieve combinational chemo-photothermal antitumor therapy.Briefly,periodic mesoporous organosilica nanoparticles（PMONs）doped with disulfide and tetrasulfide bonds were prepared by "sol-gel" method,which were utilized to simultaneously encapsulate aloe-emodin and IR820,and further modified with polyethylene glycol to obtain a stable nanodrug delivery system（denoted as Aloeemodin/IR820@PMONs-PEG）with chemo-photothermal synergistic antitumor effect.Morphology analysis,structure characterization,in vitro drug release,in vitro photothermal conversion,hemolysis assay,in vitro cell uptake,in vitro cytotoxicity assay and in vivo antitumor experiments were conducted to evaluate its physicochemical properties and antitumor efficacy.These results showed that the Aloe-emodin/IR820@PMONs-PEG nanodrug delivery systems were endowed with GSH-responsive drug release behavior,great photothermal conversion efficiency and satisfying biocompatibility as well as effective chemo-photothermal antitumor therapy.Accordingly,the mesoporous organosilica nanoparticles could be applied to encapsulate more insoluble ingredients of traditional Chinese medicine for the targeted delivery and disease treatment,which could be easily tuned by regulating the physicochemical properties of mesoporous silicon skeleton,so as to improve the druggability and therapeutic effect of traditional Chinese medicine.