Preparation Of Organic-Inorganic Hybrid Nanocarriers And Their Chemodynamic Therapeutic Properties

At present,cancer remains a major health threat for humans.The metastatic and recurring nature of tumour tissue makes it difficult to cure.Traditional chemotherapy remains the most common and effective treatment.However,the poor water solubility and short half-life in vivo of most chemotherapeutic drugs reduce the therapeutic efficacy and cause the serious side effects.As a result,several novel invasive therapeutic methods have been emerged in recent years.Chemodynamic therapy(CDT)which is usually based on a Fenton or Fentonlike reaction that converts intracellular overexpressed hydrogen peroxide(H2O2)into highly toxic hydroxyl radicals(·OH)to induce apoptosis.Compared with conventional treatments,CDT has many advantages such as non-invasive,selectivity and ignorable side effects.However,CDT also has some disadvantages which limited its therapeutic efficacy and potential clinical applications.In order to improve the efficacy of CDT,researchers have started to collaborate with other more specific therapeutic methods such as photothermal therapy(PTT)and photodynamic therapy(PDT)for multimodal synergistic treatment.With the development of nanomedicine,multi-functional nanoparticlebased drug delivery systems(nano-DDS)have received extensive attention.nano-DDS improves in vivo pharmacokinetic behaviour and enhances therapeutic efficacy while reducing side effects through the enhancement of drugs solubility and bioavailability.Based on this,we designed and prepared two organic-inorganic based hybrid nanodrug delivery systems with high drug loading rate and good biocompatibility to enhance the chemodynamic therapeutic effect and achieve efficient treatment of targeted tumours.In the second chapter of this paper,Fenton agent ferrocene(Fc)-modified mesoporous silica(MSN)was used as a nanocarrier(FMSN)and co-loaded with two functional molecules,the pro-oxidant ascorbyl palmitate(PA)and photosensitiser(IR825),to cover the targeted HA-CD onto the surface of FMSN based on the host-guest interaction between CD and Fc,forming a targeted supramolecular nanovalve(HMNP@PA&IR825).HMNP@PA&IR825 can enter tumour cells through CD44 receptor-mediated action and release functional molecules under cellular redox conditions in isolation.PA can promote H2O2 production through the oxidation process and improve the deficiency of H2O2 content in the tumour microenvironment.The Fc2+/Fc3+mixture can then catalyse excess H2O2 to generate higher cytotoxic hydroxyl radicals(·OH);on the other hand,IR825 can convert the O2 produced during CDT into another reactive oxygen species,monoclinic oxygen(1O2),through the photothermal warming behaviour under a single NIR irradiation,while the energy conversion under NIR irradiation can cause a local temperature increase in the tumour lesion.The local temperature is increased to achieve photothermal ablation-mediated apoptotic behavior.A synergistic CDT combined with PTT/PDT triple therapy is achieved.In the third chapter of this paper,we developed the ferrocene(Fc)-modified zirconium-based organic framework UiO-66-NH2 as the nano-carriers(UiO-Fc)which could load the H2S donor Pro in its porous cavities.Then the H2O2 selfsupplied macromolecule HA-CA was coated on the surface of UiO-Fc@Pro through the metal coordination interactions to construct the targeting supramolecular nanoagents(HUNP@Pro).The HUNP@Pro can reach the tumour site through the specific recognition of HA and CD44 receptors.Upon internalization by the cancer cells,HA-CA could dissociate under acidic cellular conditions to release cinnamaldehyde(CA),which promotes H2O2 production by activating NADPH oxidase.Then the Fc2+/Fc3+ mixture can catalyze excess H2O2 to generate higher cytotoxic hydroxyl radicals(·OH);on the other hand,Pro can release H2S gas through a series of reactions stimulated by cysteine(Cys)to induce cellular apoptosis.What’s more,H2S can reduce Fc3+,promoting the Fenton reaction positively and accelerating the CDT process.At the same time,it generates near-infrared fluorescence to visualize the lesion site,achieving H2Saugmented CDT.