Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
Biomaterials. 2021 Jul;274:120869. doi: 10.1016/j.biomaterials.2021.120869. Epub 2021 May 7.
Consuming glucose by glucose oxidase (GOx) has attracted great interest in cancer starvation therapy, but the therapeutic effect is severely limited by the tumor hypoxia environment. Herein, to overcome such limitation, cancer cell membranes disguised biomimetic nanoreactors were elaborately established for synergetic cancer starvation therapy and cascade amplificated hypoxia activated chemotherapy. Via a metallothionein-like self-assembly and infiltration approach, GOx and hypoxia activated prodrug banoxantrone (AQ4N) were efficiently loaded into metal-organic framework ZIF-8 nanocarriers to yield nanoreactor AQ4N/GOx@ZIF-8. Subsequently, the biomimetic nanoreactor (AQ4N/GOx@ZIF-8@CM) was obtained by camouflaging the nanoreactor with cancer cell membrane, which endowed the biomimetic nanoreactor homotypic targeting, immune escape and prolonged blood circulation features. Once targeted accumulating into tumor sites, the acid environment triggered the decomposition of ZIF-8, then encapsulated GOx and AQ4N were released. GOx would rapidly exhaust endogenous glucose and O to shut off the energy supply of tumor cells for starvation treatment. Furthermore, the aggravated tumor intracellular hypoxia environment would activate the cytotoxicity of AQ4N for chemotherapy. In vitro and in vivo results demonstrated that the designed biomimetic nanoreactor exhibited negligible systemic toxicity, besides, the combination of starvation therapy and cascade amplified hypoxia activated chemotherapy significantly inhibited the tumor growth and improved the therapeutic efficacy.
利用葡萄糖氧化酶（GOx）消耗葡萄糖在癌症饥饿治疗中引起了极大的兴趣，但治疗效果受到肿瘤缺氧环境的严重限制。在此，为了克服这种限制，精心设计了伪装成癌细胞膜的仿生纳米反应器，用于协同癌症饥饿治疗和级联放大的缺氧激活化疗。通过金属硫蛋白样自组装和渗透方法，将 GOx 和缺氧激活前药硼替佐米（AQ4N）有效地装载到金属有机骨架 ZIF-8 纳米载体中，得到纳米反应器 AQ4N/GOx@ZIF-8。随后，通过用癌细胞膜伪装纳米反应器，得到仿生纳米反应器（AQ4N/GOx@ZIF-8@CM），赋予仿生纳米反应器同型靶向、免疫逃逸和延长血液循环的特性。一旦靶向积累到肿瘤部位，酸性环境会触发 ZIF-8 的分解，然后释放封装的 GOx 和 AQ4N。GOx 会迅速耗尽内源性葡萄糖和 O2，从而切断肿瘤细胞的能量供应，进行饥饿治疗。此外，加剧的肿瘤细胞内缺氧环境会激活 AQ4N 的细胞毒性进行化疗。体外和体内实验结果表明，设计的仿生纳米反应器表现出可忽略的全身毒性，此外，饥饿治疗和级联放大的缺氧激活化疗的联合治疗显著抑制了肿瘤生长，提高了治疗效果。
