Zhu Guang, Chi Hao, Liu Meichen, Yin Yalin, Diao He, Liu Zicheng, Guo Zhaoming, Xu Weiping, Xu Jianqiang, Cui Changhao, Xing Xiao-Jin, Ma Kun
School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China.
Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
J Colloid Interface Sci. 2022 Sep;621:12-23. doi: 10.1016/j.jcis.2022.04.021. Epub 2022 Apr 12.
Ferroptosis is a newly found cell death mechanism, which could bypass apoptosis and reverse multidrug resistance of tumors. However, efficient induction of tumor ferroptosis remains a challenge. In this study, multifunctional "ball-rod" Janus nanoparticles (FTG/L&SMD) were constructed for non-small cell lung cancer (NSCLC) ferroptosis treatment. Protected by tannic acid (TA), FTG/L&SMD maintains long-term function in blood circulation, while modification by 2, 3-dimethylmaleic anhydride (DMMA) confers the FTG/L&SMD with pH-responsive charge reversal. Glucose oxidase (GOD) on FTG/L&SMD catalyzes glucose to produce HO. Then, iron ion converts HO to highly active hydroxyl radicals (OH•) via Fenton reaction, leading to lethal lipid peroxidation (LPO) accumulation. Meanwhile, TA reduces Fe to Fe to boost Fenton reaction cycle. Sor down-regulated glutathione peroxidase 4 (GPX4) expression in another pathway to induce ferroptosis synergistically. In vitro studies have shown that compared with sorafenib (Sor), FTG/L&SMD not only has more efficient tumor targeting and higher cytotoxicity, but also inhibits tumor migration. In vivo antitumor therapy experiments demonstrate that FTG/L&SMD inhibits tumor growth efficiently, and its toxicity is negligible. In general, FTG/L&SMD can initiate Fenton reaction cycle and reinforced ferroptosis to kill tumor cells, which is a promising anti-tumor nano-drug for NSCLC.
铁死亡是一种新发现的细胞死亡机制，它可以绕过凋亡并逆转肿瘤的多药耐药性。然而，高效诱导肿瘤铁死亡仍然是一项挑战。在本研究中，构建了多功能“球棒”型Janus纳米颗粒（FTG/L&SMD）用于非小细胞肺癌（NSCLC）的铁死亡治疗。在单宁酸（TA）的保护下，FTG/L&SMD在血液循环中保持长期功能，而2,3-二甲基马来酸酐（DMMA）修饰赋予FTG/L&SMD pH响应性电荷反转。FTG/L&SMD上的葡萄糖氧化酶（GOD）催化葡萄糖产生H₂O₂。然后，铁离子通过芬顿反应将H₂O₂转化为高活性羟基自由基（OH•），导致致命的脂质过氧化（LPO）积累。同时，TA将Fe³⁺还原为Fe²⁺以促进芬顿反应循环。索拉非尼（Sor）通过另一条途径下调谷胱甘肽过氧化物酶4（GPX4）的表达以协同诱导铁死亡。体外研究表明，与索拉非尼（Sor）相比，FTG/L&SMD不仅具有更高效的肿瘤靶向性和更高的细胞毒性，还能抑制肿瘤迁移。体内抗肿瘤治疗实验表明，FTG/L&SMD能有效抑制肿瘤生长，且其毒性可忽略不计。总的来说，FTG/L&SMD可以启动芬顿反应循环并增强铁死亡以杀死肿瘤细胞，是一种有前景的NSCLC抗肿瘤纳米药物。
