The Synthesis Of Two-dimensional Multifunctional Nano-enzyme And Their Application In Photothermal-based Synergistic Cancer Therapy

Since malignant tumor is a serious threat to human health,it is urgently needed to develop efficient methods for cancer therapy.The synergistic treatment strategies combining different therapeutic methods have attracted extensive attention,which can not only overcome the shortcomings of monotherapy,but also reduce the potential side effects,contributing to the synergistic effect of “1 + 1> 2”.For instance,the effect of photothermal therapy is limited by the penetration depth of light for deep tumor.While,the therapeutic effect can be significantly improved by combining photothermal therapy with radiotherapy or chemodynamic therapy.With the rapid development of nanotechnology,nano-enzyme with high catalytic activity(such as catalase and peroxidase-like)and excellent stability,can catalyze or trigger specific chemical reactions at tumor sites to regulate the tumor microenvironment(e.g.,acidity,hypoxia,glutathione and hydrogen peroxide overexpression).Worthy to mention,mild hyperthermia generated during photothermal therapy can enhance the catalytic activity of nano-enzyme to amplify the oxidative stress in tumor sites,thus improving the treatment efficiency.Herein,we developed novel two multifunctional theranostic platforms based on two-dimensional nano-enzyme,which could regulate the tumor microenvironment utilizing their enzyme-like activities.In addition,synergistic therapy based on photothermal therapy was carried out to achieve efficient multimodal image-guided tumor therapy.The details are shown as follows:In chapter 2,two-dimensional Pt Bi alloy nanosheets were synthesized by solvothermal method,followed by PEGlation to improve their dispersibility and biocompatibility(Pt Bi-PEG nanosheets).The nanosheets exhibited high near-infrared absorption capabilities,which could serve as photothermal agents.Pt Bi-PEG nanosheets could be servered as radiation sensitizers due to the remarkable X-ray absorption.Taking advantage of the catalase-like activity of platinum,Pt Bi-PEG nanosheets could continuously catalyzed the decomposition of hydrogen peroxide in tumor microenvironment to relief the hypoxia-induced radiotherapy tolerance.Moreover,the catalase-like activity could be greatly improved with the irradiation of near-infrared laser.Here,we verified the intracellular mechanism of photothermal/radiotherapy synergistic cancer therapy,which could provide both experimental and theoretical supports for the further application of Pt Bi-PEG nanosheets for in vivo cancer treatment.In chapter 3,the applications of Pt Bi-PEG nanosheets in synergistic photothermal/radiotherapy of tumor were further explored.Infrared,photoacoustic and X-ray imaging of tumor sites were performed to achieve multimodal imaging-guided precise cancer therapy.Catalytic activities of Pt Bi-PEG nanosheets in tumor sites could also be enhanced upon laser irradiation,which further relieved tumor hypoxia and enhanced the synergistic effect of photothermal/radiotherapy.In chapter 4,two-dimensional PdPtCu nanosheets were prepared by “one-pot”method,followed by PEGlation to improve their dispersibility and biocompatibility(PdPtCu-PEG nanosheets).The nanosheets exhibited peroxidase-and glutathione oxidase-like activity with the presence of copper,which could produce reactive oxygen species from hydrogen peroxide at tumor site and cause irreversible DNA damage to tumor cells.The depletion of glutathione could amplify the intracelluar oxidative stress,resulting in efficient chemodynamic therapy.Importantly,hydrogen peroxide could be decomposed to continuously produce oxygen due to the excellent catalase-like catalytic activity,which further inhibited the repairation of DNA damaged by chemodynamic therapy.PdPtCu-PEG nanosheets showed strong absorptions in the near-infrared region and could be used as photothermal agents.Upon near-infrared laser irradiation,the enzyme-like activities could be greatly improved.Here,we verified the intracellular mechanism of photothermal/chemodynamic cancer therapy of the nanosheets as multifunctional theranostic platforms with specific responses to tumor microenvironment,providing experimental and theoretical supports for the further application of PdPtCu-PEG nanosheets in the in vivo treatment of tumor.In chapter 5,the applications of PdPtCu-PEG nanosheets in synergistic photothermal/chemodynamic of tumor were further explored.Photoacoustic imaging of tumor sites was performed to achieve photoacoustic imaging-guided precise treatment.PdPtCu-PEG nanosheets still maintained remarkable catalytic activities at the tumor site,and low-power near-infrared laser irradiation could increase the temperature of tumor,which further relieved tumor hypoxia and enhanced the synergistic effect of photothermal/chemodynamic therapy.