Pd @ Pt-GOx / HA作为一种新型酶联级联纳米反应器，可有效地提高饥饿程度，增强化学动力疗法的疗效,ACS Applied Materials & Interfaces

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Pd @ Pt-GOx / HA作为一种新型酶联级联纳米反应器，可有效地提高饥饿程度，增强化学动力疗法的疗效
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-11-08 , DOI: 10.1021/acsami.0c15211
Jiang Ming ₁ , Tianbao Zhu ₁ , Wangheng Yang ₁ , Yiran Shi ₂ , Doudou Huang ₃ , Jingchao Li ₃ , Sijin Xiang ₁ , Jingjuan Wang ₁ , Xiaolan Chen ₁ , Nanfeng Zheng ₁

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葡萄糖氧化酶（GOx）介导的饥饿疗法在癌症治疗中显示出良好的应用前景。然而，缺乏葡萄糖和氧气的饥饿疗法仍然遭受一些局限，例如治疗效率低和对正常组织的潜在副作用。为了克服这些缺点，本文开发了具有可控制的酶促活性的新型酶促级联纳米反应器（Pd @ Pt-GOx /透明质酸（HA））用于高效饥饿增强的化学动力癌症治疗。Pd @ Pt-GOx / HA是通过将GOx共价缀合到Pd @ Pt纳米片（NSs）上，然后与透明质酸（HA）连接而制造的。HA对Pd @ Pt-GOx的修饰可以阻断GOx活性，Pd @ Pt的过氧化氢酶（CAT）类和过氧化物酶（POD）类活性，降低对正常细胞和器官的细胞毒性，通过主动靶向和被动增强通透性和保留（EPR）效应有效靶向CD44过表达的肿瘤。在被肿瘤细胞内吞后，细胞内的透明质酸酶（Hyase）可以分解外HA并暴露Pd @ Pt-GOx，以进行酶促级联反应。Pd @ Pt-GOx上的GOx可以催化O氧化瘤内葡萄糖₂用于癌症饥饿疗法，而Pd @ Pt分解具有CAT类活性的内源性H ₂ O ₂分解产生的O ₂可以加速GOx依赖于O ₂的葡萄糖消耗。同时，上调酸度和H ₂ ö ₂中由葡萄糖的葡萄糖氧化酶催化氧化极大地促进了所产生的肿瘤区域中的内容的pH-响应POD状的钯@铂nanozyme，然后催化的H的降解的活性₂ Ò ₂至产生大量的高毒性^• OH，从而实现了纳米酶介导的饥饿增强的化学动力学癌症治疗。体外和体内结果表明，可控的，自激活酶促级联纳米反应器施加具有可忽略的生物毒性高效抗癌作用。

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Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O₂ for cancer starvation therapy, while the O₂ produced from the decomposition of endogenous H₂O₂ by the Pd@Pt with the CAT-like activity could accelerate the O₂-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H₂O₂ content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H₂O₂ to generate abundant highly toxic ^•OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.

更新日期：2020-11-08

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