Multifunctional Mesoporous Silica Nanostructures For Tumor Theranostics

With the progresses in bio-nanotechnology and nanomedicine during the past decade,multifunctional nanocarriers that integrate diagnostic and therapeutic functions have received extensive attention.Those nanomedicine platforms are purposed to achieve two aims:precise diagnosis of the diseases at the early stage,and effective treatment with reduced side effects.As a type of biocompatible material,various silica-based nanostructures have been synthesized and shown great potential in many fields including biomedicine.Owing to their easy synthesis,tunable morphology/size,and minimal toxicity,those silica nanostructures,particularly mesoporous silica nanoparticles(MSNs),have been intensively explored for applications ranging from bioimaging to drug and gene delivery.In this dissertation,multifunctional nanoparticles based on silica are designed and fabricated,and used for multi-model imaging-guided tumor therapy,light-responsive drug release as well as tumor microenvironment modulation.The main results are as follows:Chapter 1:Recent research progresses of using silica nanoparticles for biomedical applications are reviewed in this chapter.We will introduce different types of MSN-based nanostructures which can be applied in smart stimuli-responsive controllable drug release.The motivations of our research in this dissertation are discussed.Chapter 2:Mesoporous silica nanorods intrinsically doped with photosensitizers as a multifunctional drug carrier for combination therapy of cancer.We design a novel type of mesoporous silica nanoparticles(MSNs)which are intrinsically doped with photosensitizing molecules,chlorin e6(Ce6).By increasing the amount of Ce6,the morphology of MSNs would change from spheres to rod-like shapes.Such nanorods can serve as a drug delivery carrier with high drug loading capacity by using their mesoporous structure.With doxorubicin(DOX)employed as a model drug,the combined photodynamic and chemotherapy is carried out,realizing synergistic antitumor effects.Chapter 3:Light-responsive,singlet-oxygen-triggered on-demand drug release from photosensitizer-doped mesoporous silica nanorods for cancer combination therapy.A unique type of light-responsive smart drug delivery system is developed by coating the surface of Ce6 doped mesoporous silica nanorods(CMSNRs)with bovine serum albumin(BSA)via a singlet oxygen(SO)-responsive linker,which can be cleaved by SO produced by Ce6 doped inside nanorods under 660-nm light irradiation.Using both small therapeutic molecules and larger drug-conjugated dendrimers as models,smart on-demand drug release responsive to long-wavelength light is realized.promising for combination cancer therapy with high specificity.Chapter 4:Two-dimensional magnetic WS2@Fe3O4 nanocomposite with mesoporous silica coating for drug delivery and imaging-guided therapy of cancer.We have fabricated mesoporous silica coated,iron oxide decorated WS2 nanosheets as a theranostic platform for multi-modal imaging guided combination therapy.Utilizing inherent physical properties of designed composite nanoparticles,three modal fluorescence,magnetic resonance(MR)and CT imaging are carried out on tumor-bearing mice.With a significant in vivo synergistic therapeutic effect,effective inhibition of tumor growth is realized after the combined photothermal&chemotherapy,which in the meantime exerts no obvious toxic effect to the treated animals.Chapter 5:Charge-convertible,mitochondria-targeted,catalase-loaded silica nanoshells for enhanced photodynamic therapy.We design a simple method to encapsulate catalase,which can efficiently decompose endogenic H2O2 inside the tumor microenvironment(TME)and improve tumor oxygenation,into Ce6 doped hollow silica nanoparticles.A triphenylphosphonium(CTPP)is then covalently conjugated to the surface of those nanoparticles to enhance their mitochondrial targeting ability.Those nanoparticles are further covered with a pH-responsive polyethylene glyol(PEG)grafted polymer containing dimethylmaleic acid(DMMA)groups,which can undergo charge conversion in mildly acidic TME(pH 6.8),leading to enhance cell internalization of nanoparticles and increased PDT efficacy.Chapter 6:Manganese dioxide coated WS2@Fe3O4/sSiO2 for pH-responsive MR imaging and oxygen-elevated synergetic therapy.In this system,silica nanoparticles is coated on the surface of iron oxide decorated WS2 nanosheets.A layer of manganese dioxide(MnO2),which can efficiently decompose endogenic H2O2 into oxygen,are then grown on the surface of silica shells.Owing to the presence of Fe3O4 nanoparticles as the T2 MR contrast agent,as well as the pH responsive T1 contrast offered by Mn2+decomposed from MnO2 under reduced pH,our nanocomposite can serve as a pH-responsive MR imaging.Utilizing such multifunctional nanoparticles,we are also able to realize a significantly synergistic anti-tumor effect by combined cancer radiotherapy(RT)with photothermal therapy.Chapter 7:Hollow MnO2 as a tumor microenvironment responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses.Based on silica nanoparticles as templates,we have fabricated hollow mesoporous MnO2 nanoshells,which are then modified with PEG,and loaded with two types of therapeutic molecules,Ce6 and DOX.The obtained H-MnO2-PEG/C&D with ultra-sensitive pH responsiveness enables tumor-specific MR imaging as well as efficient drug release under acidic TME pH.The relieved tumor hypoxia by MnO2-triggered decomposition of endogenous H2O2 inside tumors offers remarkable benefits not only for improving the efficacy of chemo-PDT,but also for reversing the immunosuppressive TME to favor antitumor immunities post treatment.Further combination of H-MnO2-PEG/C&D-based chemo-PDT with PD-L1 checkpoint blockade offers an abscopal effect to inhibit the growth of not only primary tumors but also distant tumors via immunotherapy.In summary,this dissertation presents a comprehensive investigation of silica-based composite nanostructures for applications in imaging-guided combination therapy,light-responsive drug release and TME modulation.Our results greatly promise further explorations of those functional nanomaterials in biomedical research.