Construction Of Tumor Microenvironment-responsive Nanozymes And Their Antitumor Research

Cancer is the leading cause of death globally.The complexity and diversity of tumors and the inevitable side effects of traditional therapies affect the therapeutic effect of tumors to a certain extent.The development of nanotechnology has brought a new dawn to tumor treatment.The development of cancer theranostic strategies using the special physicochemical properties of nanomaterials has become a hot research topic in the field of biomedicine in recent years.Nanomaterials with enzyme-like catalytic properties has been explored for cancer treatment.Utilizing the characteristics of tumor microenvironment,nanocatalytic therapy has been developed as new and effective cancer treatment strategy.Combining the enzyme-like activity of nanomaterials with their excellent optical properties,magnetic properties,and surface functionalization,a series of integrated nanoplatforms have been constructed for efficient imaging-guided tumor therapy.Herein,a multi-functional nano-therapeutic platform responsive to the tumor microenvironment has been designed and developed for combined anti-tumor therapy by photothermal enhanced nanocatalytic therapy,taking advantage of the weak acidity,hypoxia,over-expressed hydrogen peroxide and glutathione in the tumor sites.The specific research contents are as follows:(1)Ultrathin palladium-copper(PdCu)nanosheets were prepared by a liquid-phase method.The surface of the material was modified with polyethylene glycol to improve its compatibility and stability.Then,glucose oxidase(GOx)was conjugated through an amidation reaction to obtain PdCu-GOx nanosheets.The in vitro characterization of enzyme-like activity showed that PdCu-GOx had multi-enzyme activities such as glucose oxidase,catalase-like,glutathione peroxidase-like and peroxidase-like,which could realize enzymatic cascade reactions at the tumor microenvironment.The good photothermal effect of PdCu-GOx nanosheets could effectively enhance the activity of multiple enzymes,and promote the generation of reactive oxygen species,thereby providing the theoretical basis for the photothermal enhanced starvation/chemodynamic synergistic therapy.PdCu-GOx exhibited excellent enzyme-like activity at the cellular level,which could deplete the cellular glutathione and catalyze hydrogen peroxide to generate hydroxyl radicals,thereby increasing the level of oxidative stress.Upon laser irradiation,high efficient photothermal enhanced starvation/chemodynamic synergistic therapy could be achieved.The cell viability and hemolysis experiments showed that PdCu-GOx had good biocompatibility.In addition,PdCu-GOx nanomaterials showed excellent photoacoustic properties in vitro and in vivo,and could perform photoacoustic imaging of tumor sites,thereby realizing precise tumor therapy guided by photoacoustic imaging.(2)The palladium nanosheets with uniform morphology and size were synthesized by the seeded regrowth method,and gold nanoparticles were then assembled on the edge of the palladium nanosheets to obtain palladium-gold(PdAu)nanocomposites.The surface of PdAu was modified with polyethylene glycol to improve the stability and biocompatibility(PdAu-PEG).The in vitro enzyme-like activity characterization showed that PdAu-PEG had excellent catalase-like and peroxidase-like activities.PdAu-PEG showed strong absorption in the near-infrared region,and the catalytic activity of nanozymes could be enhanced upon laser irradiation,thus increasing the production of oxygen and reactive oxygen species,and alleviating tumor hypoxia and increasing the level of oxidative stress to achieve photothermal enhanced anti-tumor catalytic therapy.Moreover,PdAu-PEG nanomaterials exhibied excellent photoacoustic properties,which could enable photoacoustic imaging to guide antitumor therapy.