A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy
A biomimetic nanodrug self-assembled from small molecules for enhanced ferroptosis therapy
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DOI：
10.1039/d1bm01746b
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发表时间：
2021-12-20
影响因子：
6.6
通讯作者：
Li, Bowen
中科院分区：
文献类型：
--
作者：
Xu, Xueming;Chen, Yuan;Li, Bowen
铁凋亡药物通常诱导氧化损伤或阻断抗氧化防御，因为铁凋亡的关键机制参与癌症治疗，调节细胞内氧化还原平衡。然而，这些铁凋亡药物在体循环中不稳定，并且它们缺乏肿瘤靶向能力。在此，我们开发了一种刺激响应性和细胞膜涂层纳米药物，用于同时递送两种铁凋亡药物，一种铁螯合药物作为ROS诱导剂，另一种索拉非尼作为抗氧化酶抑制剂。在纳米药物上涂覆癌细胞膜可以增强肿瘤靶向能力并提高在血液循环中的稳定性。此外，由于动态二硒键，纳米药物在肿瘤微环境中响应谷胱甘肽（GSH）和活性氧（ROS）表现出敏感的药物释放曲线。释放的铁螯合药物和索拉非尼不仅产生羟基自由基（OH）诱导铁凋亡，而且抑制GPX4的表达，减轻铁凋亡抵抗。令人兴奋的是，这种仿生纳米药物的全身给药在荷瘤小鼠中显示出上级抗肿瘤和抗转移作用。我们的研究结果提供了一个有前途的治疗策略，共同交付的铁凋亡诱导剂和抗氧化酶抑制剂，以加强铁凋亡的治疗效果。
Ferroptosis drugs often induce oxidative damage or block antioxidant defense due to the key mechanism of ferroptosis involved in cancer treatment, regulating the intracellular redox balance. However, these ferroptosis drugs are unstable during systemic circulation, and they lack tumor-targeting capability. Herein, we developed a stimuli-responsive and cell membrane-coated nanodrug for the simultaneous delivery of two ferroptosis drugs, an iron-chelating drug as a ROS inducer and sorafenib as an antioxidase inhibitor. The coating of the cancer cell membrane over the nanodrug can enhance the tumor-targeting capability and improve the stability in the blood circulation. In addition, the nanodrug exhibits sensitive drug release profiles in response to glutathione (GSH) and reactive oxygen species (ROS) in tumor microenvironments due to the dynamic diselenide bonds. The released iron-chelating drug and sorafenib not only produce hydroxyl radicals (OH) to induce ferroptosis, but also inhibit the expression of GPX4 to mitigate the ferroptosis resistance. Excitingly, the systemic administration of this biomimetic nanodrug displays superior antitumor and anti-metastatic effects in tumor-bearing mice. Our findings provide a promising therapeutic strategy for the co-delivery of ferroptosis inducers and antioxidase inhibitors to strengthen the therapeutic efficacy of ferroptosis.