Mesoporous Silica-based Nanoplatforms For Tumor Therapy

Smart drug delivery systems based on mesoporous silica nanomaterials could be sensitive to diverse internal or external stimuli.The nanovalves would be open selectively in tumor tissues,leading to maximized therapeutic efficiency and minimized side effects.Moreover,mesoporous silica-involved hybrid nanomaterials have great potential in tumor accumulation,tumor imaging,as well as drug-controlled release.We have designed and constructed a series of smart drug delivery systems based on mesoporous silica for tumor therapy.Detailed contents are as follows:In Chapter 1,we mainly introduced the application of mesoporous silica based drug delivery systems for tumor therapy,and outlined a series of classical nanovalves for mesoporous silica nanomaterials.Then,the advantages and application of several mesoporous silica-involved hybrid nanomaterials were discussed.In Chapter 2,a mesoporous silica-based multifunctional theranostic nanoplatform（designated as MMTNP）was constructed.After loaded with anticancer drug camptothecin,the mesoporous silica nanoparticles（MSNs）were anchorded with matrix metalloproteases-2（MMP-2）activated fluorescence imaging peptides and tumor targeted c RGD peptides.Before arriving at tumor tissues,fluorescence of 5（6）-carboxytetramethylrhodamine hydrochloride（TAMRA）was remarkably quenched by 4,4-dimethylamino-azobenzene-4’-carboxylic acid（Dabcyl）.When the nanoparticles were uptaken by tumor cells via receptor-mediated endocytosis,the peptide substrate were cut off,leading to the fluorescence recovery and drug release.The enzyme activated fluorescence recovery and drug release profiles were investigated in vitro.In Chapter 3,a ROS-triggered accelerated drug delivery nanosystem（T/D@RSMSNs）was designed based on the positive feedback strategy to augment the intracellular concentration of reactive oxygen species（ROS）.The anticancer drug doxorubicin（DOX）and ROS generating agentsα-TOS were co-loaded in mesoporous silica nanoparticles.Subsequently,then nanovalveβ-cyclodextrin（β-CD）was anchored on the surface of MSNs through ROS-sensitive linkers.Finally,adamantane conjugated poly（ethylene glycol）chain was modified via host-guest interaction to enhance the stability and circulation time of nanosystems.In vitro and in vivo studies demonstrated that T/D@RSMSNs could selectively release drug in tumor cells with relatively high concentration of H₂O₂,and utilize the releasedα-TOS to augment the intracellular concentration of reactive oxygen species（ROS）,leading to the acceleration of DOX release and enhanced chemotherapy.In Chapter 4,the multifunctional mesoporous silica shell was used to stabilize the liquid metal nanoparticles（LM）to obtain a higher photothermal conversion efficiency and photothermal stability.The mesoporous silica coated liquid metal nanoparticles（LM@MSN）were further used as nanocarriers for photothermal-involved combinational therapy.The DOX loaded mesoporous silica was coated with the hyaluronic acid to inhibit the drug premature leakage and realize tumor targeting（LM@MSN/DOX@HA）.In vitro and in vivo experiments proved that LM@MSN/DOX@HA could accumulate in tumor tissues efficiently and release enzyme-responsive drug release.After being irradiated by near-infrared light,produced hypothermia and chemotherapy could inhibit the growth of tumor significantly.In Chapter 5,mesoporous silica coated Prussian blue nanoparticles were employed to enhance oxidative damage of tumor.The MTH1 inhibitor TH287 loaded mesoporous silica was further anchored with photosensitizers Zn-Por through acid-responsive linkers（PMPT）.In vitro and in vivo experiments indicated that PB core could catalyze the intracellular H₂O₂to oxygen,thus alleviate the hypoxic tumor environment,leading to an enhanced photodynamic therapy.Besides,TH287 could efficiently inhibit the inherent DNA damage repair mechanisms in tumor cells to further enhance oxidative damage of tumor.