Construction And Application Of Multifunctional Inorganic Nanocarriers

Smart nano drug delivery systems(drug delivery systems,DDSs)are able to effectively deliver antitumor drugs to tumor sites and release drug molecules under specific stimuli.Importantly,multifunctional modification further provides guarantees for efficient therapeutic effect.Given the excellent physical/chemical properties of inorganic nanomaterials,we here designed and constructed a series of multifunctional inorganic nanocarriers for antitumor research.Detailed contents are as follows:In chapter one,we reviewed the progress of multifunctional nanocarriers in cancer therapy and summarized a series strategies for multifunctionalization,including drug loading,shielding protection,targeting modification,intelligent response,and the integration of multifunctions.Part of inorganic nanomaterials with unique characteristics and application prospects were also introduced.In chapter two,a multifunctional envelop-type drug delivery system(DDS)was designed and synthesized based on mesoporous silica nanoparticle(MSNs)for synergistic tumor therapy.MSNs were used as drug reservors to load topotecan(TPT).Thereafter,mitochondria-targeted therapeutic agent(TPep)was decorated on the nanoparticles via disulfide linkage,followed by coating a charge reversal polymer with shielding effect via electrostatic interaction,obtaining the envelop-type redox-sensitive DDS.The redox-responsive drug release,tumor acidity triggered endocytosis,and synergistic antitumor effect were carefully investigated.In chapter three,a mesoporous silica/gold(MSN/Au)nanocomposite was designed for indicator-guided photo-controlled drug release study.Drug molecules were loaded into photo-switchable azobenzene(Azo)functionalized MSN.On the other hand,a peptide compound(FAM-GGPLGLAC)containing carboxyfluorescein(FAM)and MMP-2 substrate peptide as well as Ad-PEG-SH were decorated on gold nanoparticles(AuNPs),obtaining the fluorescencent indicator.Thereafter,?,?cyclodextrin(CD)dimer is used to connect these two nanoparticles,yielding the hybrid nanocomposite.Specifically,the quenched fluorescence of FAM by AuNPs could be recovered by tumor specific MMP-2,which could be used as a tumor indicator to guide the subsequent photo-controlled drug release.Subsequently,UV light was applied to induce conformation change of Azo for dissociating with CD,resulting in drug release.The indication effect,intracellular photo-controlled drug release,and cancer killing effect were evaluated both in vitro and in vivo.In chapter four,a versatile theranostic nanoplatform was designed based on mesoporous silica nanoparticles(MSNs)for tumor-targeted therapy.By sequential growth of targeting polymer(HA-CD)and photosensitizer(TPPS4)onto drug(TPZ)loaded MSN via layer-by-layer assambly,enzyme-responsive nanocarrier was obtained with the formation of supramolecular photosensitizers(supraPSs)within the multilayer.Meanwhile,paramagnetic Gd3+ was also introduced in the nanoplatform for MR imaging.Distinctive advantages include specific tumor targeting,enzyme-responsive drug release,dual-model imaging,and synergistic therapy.In vitro and in vivo experiments proved the high-performance synergistic antitumor effect of supraPSs-based PDT and biological reduction chemotherapy.In chapter five,a multifunctional theranostic nnaoplatform was designed based on magnetic mesoporous silica nanoparticles(MMSNs)for precise therapy.MMSNs were obtained by coating superparamagnetic Fe3O4 core with mesoporous silica shell.Thereafter,doxorubicin(DOX)was entrapped in the porous structure and ?-CD was immobilized on the surface of nanoparticles via platinum(IV)prodrug linker,which could be reduced to platinum(II)drug by intracellular reductants and induce DOX release.Finally,active targeting peptide(AD-PEGs-GRGDS)was assembled on the surface of nanoparticles via host-guest interaction between AD and ?-CD.This nanoplatform could specifically target tumor cells and release therapeutic agents(cisplatin and DOX)intracellularly.Thus,tumor-targeted MR imaging and synergistic antitumor effect could be ahiceved.In chapter six,an inhibitor delivery system was designed based on gold nanorods(GNRs)for enhanced photothermal therapy(PTT).GNRs were used as PTT agents,followed by decoration with a diclofenac(DC)modified hyaluronic acid(HA)polymer to achieve GNR/HA-DC.DC is a specific inhibitor towards Glutl,which could be released by the trigger of tumor overexpressed hyaluronidase(HAase).Subsequently,the liberated DC would down-regulate Glutl level,inhibit the glucose metabolism,decrease ATP-dependent HSPs production.Such a cascade effect would make cancer cells out of protection under heat treatment and more likely to be killed in PTT,inducing much enhanced therapeutic effect.