Construction Of Layered Double Hydroxide Nano Drug-loading System Based On Tumor Microenvironment For Cancer-specific Diagnosis And Treatment

Cancer is one of the most threatening diseases to human life,the widely used chemotherapy,surgery,radiation therapy and other treatments have serious side effects and damage to normal tissues in the anti-cancer process.Therefore,researchers are eager to develop a new type of treatment.The tumor microenvironment(TME)has high H2O2 and glutathione(GSH)levels,low pH and hypoxia.At present,researchers have developed specific treatments using in situ reactions of tumor regions using nanomaterials,which have the advantages of high efficacy and side effects,and are expected to become new treatment options for cancer prevention.However,the currently developed nanomaterials also have the disadvantages of single function and complicated material synthesis.To develop a multi-functional,simple preparation,and make full use of critical TME-specific diagnosis and treatment of the material,because of new treatment options depend on the development and promotion of new materialsLayered double hydroxides(LDHs)are an important class of two-dimensional nanomaterials.Due to their tunability of the main layer,large specific surface area and good biocompatibility,they can be applied to biomedical materials.The variable valence state of the transition metal and good imaging function can realize the regulation and specific diagnosis and treatment of the TME.In this thesis,the two-dimensional materials of transition metal LDHs were designed based on the comprehensive utilization of TME for specific diagnosis and treatment.Ultrathin transition metal LDHs were synthesized by a "bottom-up" approach studied by our research group to fully utilize and improve the tumor microenvironment to achieve specific treatment.The use of electrostatic forces,hydrogen bonding to load guest molecules such as photosensitizer Ce6,glucose oxidase(GOD),and construct a new specific nanoplatform for TME-specific diagnosis and treatment.Ultrathin structures were explored to have more active sites to provide in situ reactions in the TME.The relationship between the transition metal LDHs and the TME has been explored,and the theoretical basis for fiurther application of specific diagnosis and treatment is provided.The main research contents of this thesis are as follows:1.Ultrathin layered double hydroxides:toward an outstanding tumor microenvironment responsive synergetic therapyCoMn-LDHs ultrathin nanosheets were synthesized via a bottom-up method with a thickness of about 1.1 nm followed by a surface modification with a photosensitizer Ce6,which exhibited outstanding performances including T1/T2-weighted magnetic resonance(MR),photoacoustic(PA)cancer imaging as well as TME-responsive photodynamic and chemodynamic synergetic therapy(PDT/CDT).Due to the large specific surface area,CoMn-LDHs ultrathin material achieves a loading of Ce6 as high as 93.6 wt.%,and the as-prepared Ce6/CoMn-LDHs material shows GSH-responsive Ce6 release and GSH-specific PDT/CDT performance.Moreover,Ce6/CoMn-LDHs nanosheets display a satisfactory PA imaging and GSH-enhanced MR imaging with a 45.1-fold T1-enhancement.In addition,both in vitro and in vivo therapeutic tests based on Ce6/CoMn-LDHs demonstrate an outstanding anticancer activity with a complete cancer cell apoptosis and dramatic tumor elimination.This work provides a new perspective for the design of multifunctional 2D ultrathin nanosheets toward a fully promoted TME-responsive synergetic therapy,which holds great promises for future clinical cancer diagnosis and treatment.2.Ultrathin copper-iron layered double hydroxides toward tumor microenvironment responsive photothermal therapy and chemodynamic therapy.GOD/CuFe-LDH as chemodynamic therapy(CDT)and photothermal therapy(PTT)reagent achieve responsive treatment of weak acid in tumor environment.As a nanomaterial platform for tumor-specific treatment,it takes full advantage of the intrinsic properties of TME to promote synergistic treatment of CDT/PTT.Due to the sensitive response of hydrotalcite to pH,GOD/CuFe-LDH can achieve excellent photothermal performance under weakly acidic conditions.The photothermal conversion efficiency can reach 83.2%at pH=5.4 compared with neutral(46.0%).The photothermal conversion efficiency under the conditions has been greatly improved.At the same time,GOD/CuFe-LDH can consume glucose in situ to generate hydrogen peroxide.Under weakly acidic conditions,the catalytic decomposition of hydrogen peroxide by CuFe-LDH produces strong oxidizing hydroxyl radicals to kill cancer cells.On the other hand,the effect of CDT was promoted by PTT,and the synergistic effect of PTT/CDT showed significant apoptosis of Hela cells.Therefore,the GOD/CuFe-LDH nanosystem provides a new idea for the specific treatment based on TME response,and its good biocompatibility has the prospect of clinical medical research and cancer treatment.In summary,two kind of ultrathin transition metal LDHs were prepared in this paper.Ultrathin CoMn-LDHs fully utilized the TME through the photosensitizer Ce6 to achieve specific synergistic treatment of CDT/PDT and self-enhanced MRI in tumor area.Ultrathin CuFe-LDH achieves the in-situ generation of H2O2 through the combination with GOD,which solves the problem of low CDT efficiency.Moreover,PTT by near-infrared light irradiation achieves synergistic therapy for enhancing CDT.This has important guiding significance for the development of new specific diagnostic materials.