The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, P. R. China.
Adv Healthc Mater. 2019 May;8(10):e1801627. doi: 10.1002/adhm.201801627. Epub 2019 Apr 3.
Tumor microenvironment activated nanodevices have remarkable superiority to enhance therapeutic efficacy and minimize side effects, but their practical applications are dramatically reduced by the low abundance and heterogeneous distribution of specific stimuli at the tumor site. Herein, programmable vesicular nanodevices based on the triblock copolymer containing poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) with peroxalate esters (PO) as hydrogen peroxide-responsive linkage (PEG-PO-PCL-PO-PEG), are developed for co-delivery of hypoxia-activated prodrug (AQ4N) and glucose oxidase (GOD). The obtained nanodevices (PAG) can be activated by the high level of H O in tumor microenvironment to improve the permeability of membranes for glucose entrance. Afterward, the oxidation of glucose catalyzed by GOD produces amplified H O amounts which in turn induce complete destruction of PAG for fast release of AQ4N and GOD. Ultimately, the PAG can exert programmable therapeutic effects from the following aspects: 1) starvation therapy by cutting off the energy supply from glucose through GOD catalysis; 2) oxidative cytotoxicity after H O amplification; 3) chemotherapy of AQ4N activated by the intensified tumor hypoxia microenvironment after oxygen consumption. The stimuli amplification, controlled drug release, synergistic therapy, and corresponding mechanisms of PAG are demonstrated. Therefore, the presented work could provide significant new insights for cancer treatment.
肿瘤微环境激活的纳米器件在增强治疗效果和最小化副作用方面具有显著优势，但由于肿瘤部位特定刺激物的丰度低和异质性分布，其实际应用受到极大限制。在此，开发了基于含有聚乙二醇（PEG）和聚己内酯（PCL）的嵌段共聚物的可编程囊泡纳米器件，该共聚物具有过氧酸盐酯（PO）作为过氧化氢响应连接物（PEG-PO-PCL-PO-PEG），用于缺氧激活前药（AQ4N）和葡萄糖氧化酶（GOD）的共递送。所得纳米器件（PAG）可以被肿瘤微环境中的高水平 H2O2 激活，以提高葡萄糖进入的膜通透性。之后，GOD 催化葡萄糖氧化产生放大的 H2O2 量，进而导致 PAG 的完全破坏，从而快速释放 AQ4N 和 GOD。最终，PAG 可以从以下几个方面发挥可编程治疗效果：1）通过 GOD 催化切断葡萄糖的能量供应来进行饥饿治疗；2）H2O2 放大后的氧化细胞毒性；3）在耗氧后增强的肿瘤缺氧微环境中激活 AQ4N 进行化疗。本文证明了 PAG 的刺激放大、控制药物释放、协同治疗和相应的机制。因此，这项工作为癌症治疗提供了重要的新见解。
