ACS NANO.2019.

天然葡萄糖氧化酶（GOx）已成为癌症治疗中的“明星”酶催化剂，因为它可以特别有效地催化β-D-葡萄糖的氧化反应，生成葡萄糖酸和H2O2。 肿瘤通过消耗葡萄糖营养物质而产生，但是生成的H2O2可以进一步用于其他癌症治疗，例如气体疗法，金属离子疗法和化学动力疗法（CDT），从而实现多模式癌症协同治疗。 这种多式联运的疗法可能会比每种单药疗法产生更强的治疗效果。CDT被认为是一种有前途的癌症疗法，它基于产生高毒性的羟基自由基（•OH）杀死癌细胞。••OH可以直接由各种金属离子（例如Fe2 +，Cu +，M n2 + ，C r4 +和V2 +）介导的Fenton或Fenton样反应在肿瘤部位分解H2O2.GOx介导的葡萄糖消耗和H2O2的产生可以加速这一过程;因此CDT有望与GOx介导的饥饿疗法结合诱导有效的肿瘤消除。到目前为止，在这方面已经发表了几部作品。例如，Zhanget等。通过将GOx包裹在沸石咪唑酯骨架中，然后用金属多酚网络覆盖NPs，构建了一个自动催化的Fenton纳米系统。当被癌细胞内吞时，GOx催化将内源性葡萄糖氧化成大量的H2O2，释放出的单宁酸可以加速Fe3 + / Fe2 +的转化，可以保证Fe2 +介导的Fenton反应，从而增强CDT和饥饿疗法。在另一种情况下，开发了一种包含多药前体，超小型Fe3O4NPs和GOx的治疗性聚合物核纳米反应器，以将饥饿疗法，CDT和喜树碱诱导的化学疗法整合在一起，以实现协同癌症疗法。通过使用光热增强型顺序纳米催化剂GOx @ Fe3O4 @ polypyrrole进行光热/ CDT协同治疗。尽管这些治疗策略均取得了良好的抗癌效果，但在治疗中（3周内）副作用却很低，但是这些纳米平台的制备非常复杂。更重要的是，通过物理吸附或结合在其表面上的GOx负载可能会遭受潜在的长期毒性，这可能会阻碍其进一步的应用和临床转化。

MnCAP可以在酸性TME下降解，从而释放有效载荷，包括GOX，DOX和MN2 +离子。在GOX的催化下，癌细胞内的葡萄糖被氧化为葡萄糖酸和H2O2，诱导富含H 2 O 2的微环境。随后，通过Mn离子介导的类Fenton反应能够催化过氧化氢产生活性羟基自由基杀死肿瘤细胞（CDT），而且释放的多柔比星通过化疗的方法也能杀死细胞。此外，由于葡萄糖酸的生成导致pH减小又可以加速纳米粒子的降解，并促进Mn离子介导的类Fenton反应增加•oh的生成。同时，所释放的Mn2 +离子具有高的纵向弛豫（r1）值，可用于磁共振成像（MRI）以监测治疗过程。因此，通过级联反应实现了由MRI监测的协同癌症治疗，所述级联反应包括通过葡萄糖耗竭的饥饿疗法，通过Mn2 +介导的Fenton样反应的CDT和通过释放的DOX的化学疗法。DOX加载的GOX-MNCAP纳米移位具有优异的生物降解性和生物相容性，具有治疗癌症的临床潜力。

The natural glucose oxidase (GOx) has become a“star”enzyme catalyst involved in cancer treatment, since it can specially and efficiently catalyze the oxidization reaction ofβ-D-glucose to generate gluconic acid and H2O2.4Not only can this catalytic reaction starve the tumors by the consumption of glucose nutrients, but the generated H2O2can be further used for other cancer therapies, such as gas therapy,5metal-ion therapy,6and chemodynamic therapy (CDT),7resulting in a multimodal cancer synergistic treatment. Such multimodal treatment may induce a stronger therapeutic effect than that of each monotherapy.CDT is recognized as a promising cancer therapy, which is based on the generation ofhighly toxic hydroxyl radicals (•OH) to kill cancer cells.The•OH can be directly produced by various metal ion (e.g., Fe2+,C u+,M n2+,C r4+, and V2+)-mediated Fenton or Fenton-like reactions to decompose H2O2in the tumor site.Such a process can be accelerated by GOx-mediated glucose consumption and H2O2production;thus, CDT is expected to combine with GOx-mediated starvation therapy to induce effective tumor elimination. Up to now, several works have been published in this regard. For instance, Zhanget al. constructed an autocatalytic Fenton nanosystem by encapsulating GOx in a zeolitic imidazolate framework and then coating the obtained NPs with a metal polyphenol network.When endocytosed by cancer cells, the endogenous glucose was oxidized into plenty of H2O2by GOx catalysis, and the released tannic acid could accelerate Fe3+/Fe2+conversion, which could guarantee the Fe2+-mediated Fenton reaction, resulting in enhanced CDT and starvation therapy. In another case, a therapeutic polymersome nanoreactor containing polyprodrug, ultrasmall Fe3O4NPs, and GOx was developed to integrate starvation therapy, CDT, and camptothecin-induced chemotherapy together to realize a cooperative cancer therapy.More recently, Shi and co-workers reported tumor starvation/photothermal/CDT synergistic therapy by using a photo-thermal-enhanced sequential nanocatalyst of GOx@Fe3O4@polypyrrole.18Although these therapy strategies achieved good anticancer outcome with low side effects in their treatments (within 3 weeks), the preparation of these nanoplatforms is complicated. More importantly, the loading of GOx by physical adsorption or conjugation on their surface may suffer from the potential long-term toxicity, which may hinder their further applications and clinical translation.

In the study, upon internalization of GOx-MnCaP-DOX by cancer cells, the MnCaP could be degraded under acidic TME, thus releasing the payloads, including GOx,DOX, and Mn2+ions. Under the catalysis of GOx, the intratumoral glucose was oxidized to produce gluconic acid and H2O2, inducing a H2O2-rich microenvironment. Subsequently, the elevated H2O2was converted into highly toxic •OH by the released Mn2+ionsviaa Fenton-like reaction for CDT, and the released DOX could further kill the cancer cells by chemotherapy. Moreover, the pH decrease due to the gluconic acid generation would in turn accelerate the degradation of MnCaP and promote the Mn2+-H2O2reaction for an increased•OH generation. Meanwhile, the released Mn2+ions with high longitudinal relaxation (r1) value can be used for magnetic resonance imaging (MRI) to monitor the treatment process. Accordingly, the MRI-monitored cooperative cancer therapy is realizedviathe cascade reactions including starvation therapy by glucose depletion, CDT by Mn2+-mediated Fenton-like reaction, and chemotherapy by the released DOX. Importantly, all the components of the obtained nanotheranostics are biodegradable and bioabsorbable materials; thus they are promising for clinical translation.

Doi/10.1021/acsnano.9b05836

李永博