Construction And Characterization Of Stimuli-Responsive Mesoporous Silica-based Drug Delivery Systems

Cancer is one of the leading causes of human death globally,and it is a major challenge that current medical research is facing.With the rapid development of nanomaterials,the application of nanomedicine to the field of tumor therapy has attracted widespread attention in recent years.Compared with conventional medicine,nanomedicines can improve drug efficacy and lower the side-effects by utilizing the shielding effect of the carrier for drug protection,inheriting the passive targeting of the carrier(e.g.,EPR effect),and achieving drug released under precise control.Among them,stimulus-responsive nano-delivery systems utilize the properties of tumor microenvironment or signals from external field sources(e.g.,light,magnetic field,ultrasound,etc.)to provide higher efficiency,specificity,and biosafety in cancer therapy,and have promising clinical applications.In this dissertation,we demonstrated several mesoporous silica-based nano-drug delivery systems that are reactive to the tumor microenvironment and external signals,including:(1)multi-cavity organosilica nanoparticles with charge reversal properties responsive to tumor weakly acidic microenvironment;(2)organic silica nanocapsules for drug delivery with redox-triggered biodegradation responsive to the high concentration of glutathione(GSH)in cancer cells;(3)NIR-responsive hollow carbon nanospheres with tunable hierarchical pores based on dendritic silica for drug,gene,and photothermal synergistic cancer therapy;and(4)NIR light-driven nanomotors with a semi-yolk@spiky-shell structure for enhanced chemotherapy and photothermal synergistic therapy of breast cancer.The main contents are as follows:(1)Thioether-bridged mesoporous organosilica nanocapsules with pH-triggered charge reversal for drug delivery.In this study,we fabricated a hybrid nanocapsule with a negative-to-positive charge-reversal outer layer switched by the weak acidity in the tumor microenvironment.The short branched polyethyleneimine(PEI)with a positive charge and hexahydrophthalic anhydride(HHPA)with negative charge was successively modified on the surface of small uniform thioether-bridged hollow mesoporous silica nanospheres with multiple cavities(4S-HMSNs).The amide bond formed between PEI and HHPA is stable at a physiological environment(pH 7.4),and the surface presents negatively charged.While under the weakly acidic condition(pH 6.0)in the tumor,the amide bond is hydrolyzed to regenerate the amine groups of PEI,and the nanoparticles become positively charged.The electrostatic interaction between positively charged nanocapsules and negatively charged cell membranes can promote efficient cellular uptake and increase the accumulation of DOX in the cancer cells.The surface functionalization of hybrid nanocapsules provides new opportunities for the development of silica-based hybrid nanosystems for drug delivery.(2)One-pot synthesis of redox-triggered biodegradable hybrid nanocapsules with a disulfide-bridged silsesquioxane framework for promising drug delivery.We synthesized hollow organosilica nanocapsules with disulfide bonds in the framework in a one-pot method and integrated the fluorescent molecule fluorescein isothiocyanate(FITC)into the framework through a co-condensation strategy to facilitate the fluorescent tracking of the nanoparticles.As a reducing agent,the higher concentration of GSH in tumor cells can trigger the biodegradation of HSNs-4S-FITC/PEG@DOX,accelerating the release of drugs and the clearance of the carriers.The pH-and GSH-responsive release behaviors of the drug delivery system effectively increase the accumulation of DOX and significantly inhibit the growth of A549 cells.The research on regulating the structure and surface functionalization of organic-inorganic hybrid nanocapsules provides new opportunities for the development of silica-based degradable nanocarriers,which are promising for drug delivery.(3)Hollow carbon nanospheres with tunable hierarchical pores based on dendritic silica for drug,gene,and photothermal synergistic cancer treatment.Multifunctional drug carriers that integrate multiple anticancer treatment modes have a promising development prospect in cancer therapy.We used dendritic mesoporous silica as a template to form porous hollow carbon nanospheres(PHCNs)after RF coating,silica etching,and carbonization.The PEI and PEG functionalized PHCNs(PHCNs-PEI-PEG)have good biocompatibility and high co-loading capacities of DOX(482?g)and BAG3-siRNA(44 ?g).In addition,the carriers can co-deliver drug and gene into cancer cells and achieve efficient synergistic treatment.PHCNs-PEI-PEG@DOX@BAG3-siRNA can not only achieve the controlled drug release of pH and NIR responsive but also interfere with the expression of BAG3 protein in cells,realizing tumor chemotherapy,photothermal,and gene synergistic therapy.This work has shown excellent therapeutic effects and has broad prospects in the field of tumor therapy.(4)Cancer cell membrane camouflaged semi-yolk@spiky-shell nanomotors for enhanced cell adhesion and synergistic photothermal/chemotherapy of breast cancer.We demonstrated a near-infrared(NIR)light-driven biomimetic nanomotor with semi-yolk@spiky-shell structure and camouflaged with MCF-7 breast cancer cell membrane(i.e.,mC@SiO2@DOX).Such biomimetic nanomotors display efficient self-thermophoretic propulsion due to a thermal gradient generated by asymmetrically spatial distribution.Moreover,the MCF-7 cancer cell membrane coating can remarkably reduce the bioadhesion of nanomotors in biological medium and exhibit highly specific self-recognition of the source cell line.The combination of effective propulsion and homologous targeting dramatically improves cell adhesion and the resultant cellular uptake efficiency in vitro from 26.2%to 67.5%,obviously increasing the accumulation of the nanomotors in the cells.Therefore,the biomimetic mC@SiO2@DOX displays excellent synergistic photothermal and chemotherapy with over 91%MCF-7 cell growth inhibition rate.Such smart design of the fuel-free,NIR light-powered biomimetic nanomotors may pave the way for the application of self-propelled nanomotors in biomedicine.