Chen Ruie, Wen Liewei, Guo Feng, He Jiawen, Wong Ka Hong, Chen Meiwan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China; Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital (The Affiliated Hospital of Beijing Institute of Technology), Beijing Institute of Technology, Zhuhai 519088, China.
J Control Release. 2025 Mar 10;379:866-878. doi: 10.1016/j.jconrel.2025.01.026. Epub 2025 Jan 29.
Nanomedicine-driven ferroptosis has emerged as a promising tumor treatment strategy through delivering exogenous iron and aggravating the lethal accumulation of lipid peroxides (LPO). However, the compensatory mechanisms of ferroptosis defense systems in cancer cells compromise the therapeutic efficacy and lead to potential side effects. Herein, a highly effective ferroptotic nano-amplifier is designed to synergistically promote ferroptosis via increasing intracellular labile iron, exacerbating lipid peroxidation and overcoming the defense system. Briefly, a natural-derived amphiphilic polymer composing of chondroitin sulfate (CS), arachidonic acid (AA) and a redox-sensitive linker, cystamine (CYS) is constructed to self-assemble as a GSH-responsive nanodrug delivery system for loading bioactive ingredient Polyphyllin I (PPI) and ferric ion (Fe). This nanodrug (CSAA/Fe@PPI) can scavenge the aberrant intracellular GSH via CYS linker, accompanied with the degradation of CSAA/Fe@PPI and the release of PPI, AA and Fe. On one hand, the intracellular labile iron level is significantly elevated due to the exogenous delivery of Fe and PPI-induced ferritinophagy. On the other hand, ROS burst and the supplement of AA initiate and propagate the lipid peroxidation chain reaction. Meanwhile, the depletion of intracellular GSH suppresses the GPX4 activity, further strengthening the lethal accumulation of LPO. Consequently, the ferroptotic antitumor efficacy is remarkably improved by systemically aggravating iron overload and lipid peroxidation. Therefore, our study presents an effective strategy to improve ferroptosis-based anti-cancer treatment through multiple intervention routes.
纳米医学驱动的铁死亡已成为一种有前景的肿瘤治疗策略，通过递送外源性铁并加剧脂质过氧化物（LPO）的致死性积累来实现。然而，癌细胞中铁死亡防御系统的补偿机制会损害治疗效果并导致潜在的副作用。在此，设计了一种高效的铁死亡纳米放大器，通过增加细胞内不稳定铁、加剧脂质过氧化和克服防御系统来协同促进铁死亡。简而言之，构建了一种由硫酸软骨素（CS）、花生四烯酸（AA）和氧化还原敏感连接体胱胺（CYS）组成的天然衍生两亲聚合物，使其自组装成一种对谷胱甘肽（GSH）响应的纳米药物递送系统，用于负载生物活性成分重楼皂苷I（PPI）和铁离子（Fe）。这种纳米药物（CSAA/Fe@PPI）可以通过CYS连接体清除细胞内异常的GSH，同时伴随着CSAA/Fe@PPI的降解以及PPI、AA和Fe的释放。一方面，由于外源性递送Fe和PPI诱导的铁蛋白自噬，细胞内不稳定铁水平显著升高。另一方面，活性氧（ROS）爆发和AA的补充引发并传播脂质过氧化链式反应。同时，细胞内GSH的消耗抑制了谷胱甘肽过氧化物酶4（GPX4）的活性，进一步加强了LPO的致死性积累。因此，通过全身加剧铁过载和脂质过氧化，铁死亡抗肿瘤疗效得到显著提高。所以，我们的研究提出了一种通过多种干预途径改善基于铁死亡的抗癌治疗的有效策略。
