Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

中文翻译：

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甘草次酸作为肝细胞靶向配体功能化铂 (IV) 配合物用于肝细胞癌治疗和克服多药耐药性


迫切需要有前景的靶向治疗方案来克服用于治疗肝细胞癌的铂（II）药物引起的耐药性和副作用。在此，设计并合成了六种通过连接铂（II）试剂和甘草次酸（GA）的新型多功能铂（IV）配合物。其中，复合物20对测试的癌细胞（包括顺铂耐药细胞）表现出优于顺铂的抗肿瘤活性，同时表现出良好的肝脏靶向能力。此外，复合物20可以显着引起DNA损伤和线粒体功能障碍，促进活性氧的产生，激活内质网应激，最终诱导细胞凋亡。此外，复合物20可以有效抑制HepG-2细胞的细胞迁移和侵袭，并引发自噬和铁死亡。更重要的是，复合物20在HepG-2或A549异种移植模型中表现出比顺铂或顺铂/GA组合更强的肿瘤抑制能力，且几乎没有全身毒性。总的来说，复合物 20 可以开发为一种潜在的抗 HCC 药物，用于癌症治疗。