Xu Xiang, Chen Yiwei, Zhang Yongxin, Yao Yansheng, Ji Peng
Jiangsu Key Laboratory of Chiral Pharmaceuticals Biosynthesis, College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, Jiangsu, China.
Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing 210009, China and Department of Endocrinology, the Affiliated Taixing People's Hospital of Medical College, Yangzhou University, Taixing 225400, China.
J Mater Chem B. 2020 Sep 18. doi: 10.1039/d0tb01616k.
Intracellular amplification of oxidative stress has been proved to be an effective strategy to induce cancer cell death and the Fenton reaction was regarded as a robust way to generate ROS which are the main cause of amplified oxidative stress. However, current Fenton reaction-inducing agents lacked stability in the bio-environment and failed to exert their ideal catalytic performance. We, hereby, designed an Fe2+-based metal-organic framework (MOF) to deliver Fe2+ to cancer cells to trigger the Fenton reaction and produce excessive ROS. The obtained nano-scale MOF that was constructed by ferrous acetate and organic ligands (BDC-NH2) endowed itself with excellent stability in bio-media and pH responsively degraded itself to release Fe2+ in the acid tumor microenvironment. Such a characteristic demonstrated robust capacity to catalyze the Fenton reaction and produce considerable ROS and thus induced distinct Fe2+-mediated cell ferroptosis. Meanwhile, directly exploiting an Fe2+-based MOF to inhibit and kill cancer cells circumvented the potential adverse effects of loading drugs (like the cardiotoxicity of doxorubicin, and the nephrotoxicity and ototoxicity of cisplatin) and proved to be biocompatible in in vivo experiments. More importantly, observations of the in vivo antitumor experiment attested its impressive inhibition on cancer cells and amelioration on the physical health of treated mice. Our study thus presented a novel and biocompatible ferroptosis strategy to be applied in effective clinical cancer therapy.
细胞内氧化应激的放大已被证明是诱导癌细胞死亡的有效策略，芬顿反应被认为是产生活性氧（ROS）的有效方式，而ROS是放大氧化应激的主要原因。然而，目前的芬顿反应诱导剂在生物环境中缺乏稳定性，无法发挥其理想的催化性能。在此，我们设计了一种基于Fe2+的金属有机框架（MOF），将Fe2+递送至癌细胞以触发芬顿反应并产生过量的ROS。通过醋酸亚铁和有机配体（BDC-NH2）构建的纳米级MOF在生物介质中具有优异的稳定性，并在酸性肿瘤微环境中pH响应性地降解自身以释放Fe2+。这种特性显示出强大的催化芬顿反应和产生大量ROS的能力，从而诱导明显的Fe2+介导的细胞铁死亡。同时，直接利用基于Fe2+的MOF抑制和杀死癌细胞避免了负载药物的潜在不良反应（如阿霉素的心脏毒性以及顺铂的肾毒性和耳毒性），并在体内实验中证明具有生物相容性。更重要的是，体内抗肿瘤实验的观察结果证实了其对癌细胞的显著抑制作用以及对治疗小鼠身体健康的改善。因此，我们的研究提出了一种新颖且具有生物相容性的铁死亡策略，可应用于有效的临床癌症治疗。
