Li Yifei, Han Shangcong, Zhao Yi, Yan Jianqin, Luo Kui, Li Fashun, He Bin, Sun Yong, Li Fan, Liang Yan
Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, 266073, China.
Department of Recuperation Medicine, Qingdao Special Service Sanatorium of PLA Navy, Qingdao, 266071, China.
Small. 2025 Feb;21(5):e2404299. doi: 10.1002/smll.202404299. Epub 2024 Dec 11.
Cancer cells possess an efficient redox system, enabling them to withstand oxidative damage induced by treatments, especially in hypoxia areas and ferroptosis can disrupt redox homeostasis in cancer cell. Herein, GSH-sensitive nanoparticles are constructed that induce ferroptosis by long-lasting GSH depletion and enhanced PDT. Carbonic anhydrase IX inhibitor, protoporphyrin IX (Por) complexed with Fe and epirubicin (EPI) are grafted to hyaluronic acid (HA) via disulfide bonds to obtain HSPFE and loaded xCT inhibitor SAS for fabricating SAS@HSPFE which is actively targeted to deep hypoxic tumor cells, and explosively releasing EPI, Por-Fe complex and SAS due to at high GSH concentration. Specifically, SAS inhibited the GSH biosynthesis, and the generation of ROS by Por and the involvement of Fe in the Fenton reaction jointly facilitates oxidative stress. Besides, Fe reacted with excess HO to produce O, which continuously fuels PDT. GPX4 and SLC7A11 related to antioxidant defense are down-regulated, while ACSL4 and TFRC promoting lipid peroxidation and ROS accumulation are up-regulated, which enhanced ferroptosis by amplifying oxidative stress and suppressing antioxidant defense. SAS@HSPFE NPs revealed highly efficient antitumor effect in vivo study. This study provides a novel approach to cancer treatment by targeting redox imbalance.
癌细胞拥有高效的氧化还原系统，使其能够抵御治疗诱导的氧化损伤，尤其是在缺氧区域，而铁死亡可破坏癌细胞中的氧化还原稳态。在此，构建了对谷胱甘肽（GSH）敏感的纳米颗粒，其通过持久消耗GSH和增强光动力疗法（PDT）来诱导铁死亡。碳酸酐酶IX抑制剂、与铁络合的原卟啉IX（Por）和表柔比星（EPI）通过二硫键接枝到透明质酸（HA）上，以获得HSPFE，并负载xCT抑制剂SAS来制备SAS@HSPFE，其可主动靶向深层缺氧肿瘤细胞，并在高GSH浓度下爆炸性释放EPI、Por-铁络合物和SAS。具体而言，SAS抑制GSH生物合成，Por产生的活性氧（ROS）以及铁参与芬顿反应共同促进氧化应激。此外，铁与过量的羟基反应生成氧，持续为PDT提供能量。与抗氧化防御相关的谷胱甘肽过氧化物酶4（GPX4）和溶质载体家族7成员11（SLC7A11）被下调，而促进脂质过氧化和ROS积累的长链脂酰辅酶A合成酶4（ACSL4）和转铁蛋白受体（TFRC）被上调，通过放大氧化应激和抑制抗氧化防御增强了铁死亡。SAS@HSPFE纳米颗粒在体内研究中显示出高效的抗肿瘤作用。本研究通过靶向氧化还原失衡提供了一种新的癌症治疗方法。
