Construction And Anti-tumour Properties Of Organic-inorganic Hybrid Materials Loaded With Pt Nanoenzyme

Photodynamic therapy（PDT）is a new minimally invasive treatment for tumor triggered by light.It uses a specific wavelength of light to irradiate the tumor site,and the photosensitizer absorbs the energy of the photons,partially exciting electrons.The excited photosensitizer transfers energy to oxygen in the surrounding environment,producing cytotoxic reactive oxygen species（ROS）.Thus,the three elements of PDT are photosensitizer,light,and oxygen,and none of them can be lacking.However,the existing photosensitizer-induced photodynamic therapy still suffers from the following problems:（1）The therapeutic efficacy of PDT is critically restricted by tumor hypoxia caused by the uncontrolled proliferation of cancer cells and vascular dysfunction;（2）Single-mode PDT is prone to tumor recurrence and metastasis,making it difficult to achieve efficient tumor suppression.To address the above problems,we developed two nanomaterials decorated with platinum（Pt）nanozyme.The main results are shown as follows:（1）Ce6@CuS-Pt/PEG nanomaterials for nanozyme-enhanced photodynamic and photothermal combination therapyIn order to alleviate tumor hypoxia and optimize the effect of single-mode PDT,we have constructed the Ce6@CuS-Pt/PEG nanoplatform.Firstly,we synthesized the hollow CuS nanospheres with an average diameter of～200 nm by forming Cu₂O nanoparticles and then the in-situ vulcanization reaction.Subsequently,CuS nanospheres were surface-decorated with Pt nanoparticles as nanozyme via an in-situ reduction route,followed by modifying the DSPE-PEG5000 and loading the photosensitizer Chlorin e6（Ce6）.The obtained Ce6@CuS-Pt/PEG exhibits high photothermal conversion efficiency（43.08%）,good singlet oxygen（¹O₂）generation ability,and good physiological stability.In addition,Ce6@CuS-Pt/PEG shows good catalytic performance due to the presence of Pt nanozyme,which can effectively convert H₂O₂ to O₂ and significantly enhance the production of cytotoxic ¹O₂.Under laser irradiation for 3 minutes,the degradation rate of DPBF after being treated with Ce6@CuS-Pt/PEG is up to 88.33%.When Ce6@CuS-Pt/PEG dispersion is injected into mice,its inhibition of tumor growth was significantly higher than that of single mode treatment,achieving the nanozyme-enhanced photodynamic-photothermal combination therapy.Thus,the present Ce6@CuS-Pt/PEG can act as an efficient multifunctional nanoplatform for tumor therapy.（2）DOX&ZnO₂@Zr-Ce6-Pt/PEG nanomaterials for hydrogen peroxide/oxygen self-supplied photodynamic and chemo combination tumor therapy.Employing nanozymes to convert endogenous H₂O₂ to O₂ will be an effective strategy to overcome the hypoxia of the tumor microenvironment,thereby enhancing O₂-dependent PDT performance.However,the concentration of H₂O₂（50-100μM）in the tumor is limited.In addition,PDT is also stopped once the laser is stopped.To further improve the efficacy of PDT,we synthesized the DOX&ZnO₂@Zr-Ce6-Pt/PEG multifunctional nanocomposites via a bottom-up approach for H₂O₂/O₂ self-supplying photodynamic and chemo combination therapy.Firstly,the Zr-Ce6 metal-organic hybrid nanoparticles were constructed on the surface of ZnO₂nanoparticles by ultrasound.Then,ZnO₂@Zr-Ce6 was employed as a model for the in situ growth of Pt nanocrystals,followed by DSPE-PEG5000 coating and chemotherapeutic drug doxorubicin（DOX）loading.The DOX&ZnO₂@Zr-Ce6-Pt/PEG nanocomposites can generate exogenous H₂O₂ in a weak acid environment,which will be rapidly converted to O₂ by the Pt nanozyme.And the produced O₂ enables hypoxia relief for enhanced Zr-Ce6-mediated PDT.Under laser irradiation,the amount of ¹O₂ produced by ZnO₂@Zr-Ce6-Pt is 2.8 times as many as those produced by Zr-Ce6 in the weak acid condition.Meanwhile,the efficient release of DOX confers the chemotherapy.When DOX&ZnO₂@Zr-Ce6-Pt/PEG dispersion is intratumorally injected into tumor-bearing mice,the tumors can be effectively inhibited due to the combined effect of hydrogen H₂O₂/O₂ self-supply-boosted photodynamic and chemo combination therapy which have superior therapeutic effect compared to single-mode therapy.Thus,DOX&ZnO₂@Zr-Ce6-Pt/PEG is expected to be a versatile agent to fight against cancer.