School of Materials Science and Engineering, Central South University, Changsha, Hunan 410083, China.
Department of Neurology, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
Biomater Sci. 2022 May 4;10(9):2358-2369. doi: 10.1039/d1bm01944a.
Employing hypoxia-activated prodrugs is an appealing oncotherapy strategy, but limited by insufficient tumor hypoxia. Moreover, a standalone prodrug fails to treat tumors satisfactorily due to tumor complexity. Herein, a nanosystem (TPZ@FeMSN-GOX) was established for triple synergetic cancer starvation therapy, hypoxia-activated chemotherapy and chemodynamic therapy (CDT). TPZ@FeMSN-GOX was prepared by synthesizing iron-doped mesoporous silica nanoparticles (FeMSNs) followed by surface conjugation with glucose oxidase (GOX), and then loading with hypoxia-activated prodrug tirapazamine (TPZ). When TPZ@FeMSN-GOX entered the tumor cells, GOX could not only exhaust glucose to starve cancer cells and concomitantly produce HO, but also consume O to aggravate the hypoxia environment and amplify TPZ-mediated chemotherapy. Meanwhile, the released Fe was reduced to reactive Fe by endogenous glutathione, which ultimately decomposed the produced HO and endogenous HO into highly toxic ˙OH, guaranteeing highly efficient CDT. Together, TPZ@FeMSN-GOX could effectively kill cancer cells and significantly inhibit tumor growth, providing a good paradigm for effective tumor treatment.
利用缺氧激活前药是一种有吸引力的肿瘤治疗策略，但受到肿瘤缺氧不足的限制。此外，由于肿瘤的复杂性，单一的前药不能令人满意地治疗肿瘤。本文构建了一种纳米系统（TPZ@FeMSN-GOX），用于三重协同癌症饥饿治疗、缺氧激活化疗和化学动力学治疗（CDT）。TPZ@FeMSN-GOX 通过合成铁掺杂介孔硅纳米粒子（FeMSNs），然后与葡萄糖氧化酶（GOX）表面偶联，再负载缺氧激活前药替拉扎明（TPZ）来制备。当 TPZ@FeMSN-GOX 进入肿瘤细胞时，GOX 不仅可以耗尽葡萄糖使癌细胞饥饿，并同时产生 HO，还可以消耗 O 来加剧缺氧环境并放大 TPZ 介导的化疗。同时，内源性谷胱甘肽将释放的 Fe 还原为反应性 Fe，最终将产生的 HO 和内源性 HO 分解为高毒性的˙OH，保证了高效的 CDT。总之，TPZ@FeMSN-GOX 可以有效地杀死癌细胞并显著抑制肿瘤生长，为有效的肿瘤治疗提供了一个很好的范例。
