| Cancer is a major worldwide menace to human health,which has become one of the most severe global health issues.Personalized treatment plans for cancer therapy have been at the forefront of oncology research for many years.With the advent of many novel nanoplatforms,this goal is closer to realize today than ever before.The field of nanotechnology holds great promise in cancer imaging and therapy,as novel nanoplatforms for biomedical applications are being developed at an impressive rate.Mesoporous silica nanoparticles(MSNs)-based nanomaterial possess the unique structural characters such as high pore volume,tunable pore sizes,easily modified inner/outer surfaces.interfacial effect,large surface area,easily doped amorphous skeleton composition and excellent biocompatibility.Thus,they have been extensively explored in the applications of nano-biotechnology,such as drug delivery,gene therapy,biosensors,molecular imaging,tissue engineering,etc.Over the past few years,silica-based nanotheranostics have demonstrated their great potential for nano/biomedical applications.However,the uncontrollable and difficult degradability of their pure silica framework and longtime in vivo retention still cause severe and unpredictable toxicity risks.Therefore,it is highly desirable to design and synthesize materials with safety framework structures and compositions.In view of the above application requirements in the field of nanomedicine,this thesis based on nano-synthetic chemistry,employed the synthesis of inorganic nanoparticles with tunable size,morphology and biodegradability as the starting point,focused on the functional design of nomvasive and biocompatible responsive gatekeepers,and the fabrication of biodegradable mesoporous organosilica nanotheranostics as the target.The systematic work has been carried out and the main assignment of this dissertation involves five aspects,which are summarized as follows:(1)Functionalized MoS2 nanosheet-capped periodic mesoporous organosilicas as a multifunctional platform for synergistic targeted chemo-photothermal therapy of breast cancerThe thioether-bridged periodic mesoporous organosilicas(PMOs)with tunable pore sizes were prepared according to the surfactant directed sol-gel method.The chemotherapy drug,DOX was then loaded into the channels of the PMOs.Then,the novel targeted molecular bovine serum albumin-folic acid-modified MoS2 sheets(MoS2-PEI-BSA-FA)were successfully synthesized and characterized,and then utilized as a capping agent to block PMOs to control the drug release and to investigate their potential in near-infrared photothermal therapy and drug delivery system.The resulting PMOs-DOX@MoS2-PEI-BSA-FA complexes had a uniform diameter(196 nm);high DOX loading capacity(185 mg/g PMOs-SH);excellent photothermal transformation ability;and good biocompatibility in physiological conditions.In vitro confocal laser scanning macroscopy and flow cytometry analysis confirmed that the material exhibits specificity to target tumor cells via an FA-receptor-mediated endocytosis process.The in vitro cell viability and in vivo experiments further demonstrated that the platform for synergistic chemo-photothermal therapy could significantly inhibit tumor growth,which is superior to any monotherapy.This work employed the PMOs combined with two-dimensional nanosheet to overcome the single functional defect of silica-based nanomaterials,and the nanosheets-gated strategy in this work also shows general potential for the fabrication of multifunctional nanoplatform based on other two-dimensional nanosheet modified mesoporous organosilicas.(2)Multifunctional A7R peptide-modiried hollow mesoporous silica@Ag2S nanotheranostics for photoacoustic/near-infrared fluorescence imaging-guided tumor-targeted chemo-photothermal therapyIn order to achieve higher drug loading and more sensitive stimulation-responsive drug release performance of mesoporous silica nanomaterials,we employed a "structural difference-based selective etching"strategy to control the structures of MSNs to obtain hollow mesoporous silica nanoparticles(HMSs).Then,a multifunctional nanoplatform consisting of A7R peptide(ATWLPPR)conjugated hollow mesoporous silica nanoparticles decorated with Ag2S nanodots(Ag2S@HMSs-A7R)has been developed as an efficient theranostic agent for simultaneous photoacoustic(PA)imaging and near-infrared fluorescence imaging(NIRF)-guided targeted chemotherapy and photothermal therapy against human breast cancer MDA-MB-231 cells.The design of Ag2S doped HMSs by in situ controlled growth of ultrasmall Ag2S nanodots in the mesopores of HMSs.Due to their unique nanoscale hollow architectures,the synthesized multifunctional nanoplatform exhibits high DOX loading capability(451 mg/g)and can be precisely controlled by GSH,acidic environment and external laser irradiation.Thanks to the strong tunable NIR absorbance of Ag2S,the nanoplatform produce effective photoacoustic capacity and superb photothermal conversion under light irradiation,thereby exhibiting sufficient in vivo fluorescence and photoacoustic signals as well as desirable photothermal therapeutic performance.Importantly,A7R peptide can selectively bind the Neuropilin-1(NRP-1)receptor,which overexpressed by the MDA-MB-231 cells.The achieved Ag2S@HMSs-A7R possess ideal imaging capability for both PA and NIRF imaging in vivo,and the anti-tumor effect of Ag2S@HMSs(DOX)-A7R was studied in vitro and in vivo,showing remarkable synergistic chemo-photothermal effect(combination index,Cl<1).Over all,the strategy of utilizing triple-responsive nanocarriers presents a highly promising potential as an efficient method for cancer theranostics.(3)A chemodrug-gated biodegradable hollow mesoporous organosilica nanotheranostics based on pH-sensitive dynamic covalent bond for multimodal imaging-guided low-temperature photothermal therapy/chemotherapy of cancerNoninvasive physical treatment with relatively low intensity stimulation and the development of highly efficient anticancer medical strategy are still desirable for cancer therapy.Herein biodegradable hollow mesoporous organosilica nanoparticles(HMONs)were synthesized based on the chemical homology principle and then loaded with indocyanine green(ICG)and heat shock protein 90(Hsp90)inhibitor.After capping by the gemcitabine(Gem)molecule through a pH-sensitive acetal covalent bond and modification with polyethylene glycol(NH2-PEG),the new system,which tactfully bypasses the use of auxiliary capping agents were obtained(ICG-17AAG@HMONs-Gem-PEG).The fabricated nanoplatform exhibits desirable small molecule release at the tumor tissues/cell sites and shows a reduced risk for drug accumulation.At weakly acidic pH(<6.0),the loaded ICG and 17AAG could be released ondemand with the Gem gatekeeper specifically opening due to hydrolysis of the acetal bonds.Subsequently,17AAG induces down-regulation of Hsp90 and thus reverses the thermoresistance of the tumor cells.Meanwhile,the released ICG can cause effective cancer cell apoptosis under relatively low temperatures(e.g.,41?)to achieve the aim of low-temperature photothermal therapy.Interestingly,due to the strong NIR absorption of ICG,the nanocapsules also show a strong contrast of NIR fluorescence and PA imaging for guiding the therapy.In short,this work not only presents a smart drug gated nanoplatform with pH-responsive payload release and theranostic performance but also provides an outstanding low-temperature PTT strategy,which is highly valid in the inhibition of cancer cells with minimal damage to the organism.In particular,a synergistic inhibition effect of ICG-17AAG@HMONs-Gem-PEG on tumor growth has been systematically demonstrated both in vitro and in vivo.Importantly,GSH-responsive biodegradability of HMONs,not only causes distinctive reducing microenvironment-responsive on-demand DOX release,but also ensures the fast biodegradation for guaranteeing their further clinical translation.(4)A prodrug-gated,mild hyperthermia-activated perfluoropentane loaded biodegradable hollow mesoporous organosilica nanotheranostics for ultrasound(US)/PA imaging imaging-guided synergistic chemo-photothermal therapyAming to further expand the application of mesoporous organosilica materials in theranostics,in this chapter we employed the HMONs as a nanocarrier to load indocyanine green(ICG)and perfluoropentane(PFP),simultaneously.A paclitaxel(PTX)prodrug is developed to both serve as a redox-sensitive gatekeeper controlling ICG release from the HMON pores and a chemotherapeutic.Finally,polyethylene glycol(PEG)was introduced to the surface to improve colloidal stability,yielding particles termed ICG/PFP@HMOP-PEG.When the nanocomposite enters tumor cells,the disulfide bond between the paclitaxel prodrug and the organosilica nanoparticles would be breaked at high concentrations of glutathione in tumor cells.On the one hand,this cleavage of disulfde bonds can open the gatekeeper to accurately control the release of the payloads.On the other hand,the deciduous PTX prodrugs undergo charge transfer to form free PTX molecules for chemotherapy.ICG generates mild hyperthermia upon exposure to an 808 nm laser,and this in turn leads to a liquid-gas phase transition of PFP,resulting in the generation of bubbles which can be used for ultrasound imaging.The results of US imaging showed that the achieved multifunctional NPs could act as the contrast agents for both Contrast-and B-mode US imaging,which was further demonstrated by the in vivo contrast-enhanced US imaging upon MDA-MB-231 tumor-bearing mice.The nanoparticles cause NIR-responsive hyperthermia,permitting both photothermal therapy and photoacoustic imaging.Also,the intrinsic NIR fluorescence imaging ability of ICG/PFP@HMOP-PEG permits real-time visualization of its distribution in vivo,which is conducive to both accurate diagnosis and treatment.In vitro and in vivo evaluations confrm that ICG/PFP@HMOP-PEG leads to potent and synergistic chemo-photothermal therapy.The material developed in this work thus has great potential for exploitation in advanced cancer theranostics.Furthermore,the multifunctional bubble generation nanotheranostics also allow for other oxygen-dependent treatments,such as radiotherapy and photodynamic therapy(PDT).(5)Biomineralized iridium oxide(Ir02)gated biodegradable mesoporous nanosystem for anti-inflammation and cancer theranosticsThe long-term retention of inorganic nanoparticles in the body could induce inflammation by enhancing the level of reactive oxygen species(ROS).All of these factors will significantly hamper the clinical translation of the current multifunctional contrasts.Thus,intrinsically integrating precise diagnosis,effective therapy,and self-anti-inflammatory action into a single nanoparticle is attractive for tumor treatment and future clinical application.In this chapter,we describe the development of a simple efficient capping agent based on bovine serum albumin-iridium oxide nanoparticles(BSA-IrO2),prepared in a facile manner through one-step biomineralization.Then,a tumor-specific biodegradable nanotheranostics is strategically designed based on Hsp90 inhibitor,17AAG-encapsulated HMONs,followed by pore-engineering including gating with BSA-IrO2 nanoparticles and conjugation of polyethylene glycol(PEG),yielding 17AAG@HMONs-BSA-IrO2-PEG(AHBIP)nanotheranostics for multimode computed tomography(CT)/PA imaging-guided combination low-temperature PTT and PDT of tumors.Similar to previous chapters,such nanoplatform exhibits high cargos loading(35.4%for 17AAG with high drug loading efficiency of 94%)and controllable stimuli-responsive release of 17AAG.After endocytosis by tumor cells,the BSA-IrO2 gatekeeper will be opened due to the breakage of disulfide bond.Subsequently,the released 17AAG would down-regulated the level of Hsp90 and thus reverses the thermoresistance of the tumor cells,thus could induce effective cells apoptosis under low-temperature heating.The western blotting analysis in vitro and in vivo indicates the treatment of AHBIP would cause significantly down-regulated Hsp90 expression.Importantly,the IrO2 simultaneously endows the nanotheranostics with high catalytic activity to trigger the decomposition of H2O2into O2 and thus relieving the hypoxia of cancer cells,enhancing PDT efficiency as well as protecting normal tissues against H2O2-induced inflammatory.Also,AHBIP nanoplatform possesses remarkable performance on CT and PA imaging.Notably,such biodegradable nanosystems exhibit desirable therapeutic efficiency under a single NIR laser irradiation owing to PDT and low-temperature PTT synergistic treatment,which has been demonstrated both in vitro and in vivo.Furthermore,AHBIP nanoparticles also exhibited a long blood circulation time(5.14 h)and high tumor accumulation(12 h:8.54%ID/g).Due to the theranostics agent is purely composed by biocompatible and biodegradable components,it is highly expected that the designed AHBIP may indeed be a theranostic nanoplatform for multimode imaging-guided combination therapy of different types of tumors and possess substantial potential for translational nanomedicine applications.In summary,this dissertation,we have systematically studied the biomedical applications of mesoporous organosilicas and functionalized nanocomposites,particularly for imaging,chemotherapy,photothermal and photodynamic therapy of cancer,and carefully investigated the synthesis of biodegradable organic/inorganic hybrid silica nanomaterials and design of controlled gatekeepers.Our results greatly promote mesoporous organosilica-based biomedical research,and provide helpful guidelines for the future explorations of other functional nanomaterials in cancer theranostics. |
PDF Full Text Request