Wei Dengshuai, Yu Yingjie, Zhang Xingcai, Wang Yongheng, Chen Hao, Zhao Yao, Wang Fuyi, Rong Guanghua, Wang Wenwen, Kang Xiang, Cai Jing, Wang Zehua, Yin Ji-Ye, Hanif Muhammad, Sun Yongbing, Zha Gaofeng, Li Linxian, Nie Guohui, Xiao Haihua
Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
ACS Nano. 2020 Dec 22;14(12):16984-16996. doi: 10.1021/acsnano.0c06190. Epub 2020 Dec 7.
Excessive oxidative stress in cancer cells can induce cancer cell death. Anticancer activity and drug resistance of chemotherapy are closely related to the redox state of tumor cells. Herein, five lipophilic Pt(IV) prodrugs were synthesized on the basis of the most widely used anticancer drug cisplatin, whose anticancer efficacy and drug resistance are closely related to the intracellular redox state. Subsequently, a series of cisplatin-sensitive and drug-resistant cell lines as well as three patient-derived primary ovarian cancer cells have been selected to screen those prodrugs. To verify if the disruption of redox balance can be combined with these Pt(IV) prodrugs, we then synthesized a polymer with a diselenium bond in the main chain for encapsulating the most effective prodrug to form nanoparticles (NP(Se)s). NP(Se)s can efficiently break the redox balance simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis RNA-seq was employed to provide a comprehensive understanding of the changes in transcriptome and the alterations in redox-related pathways in cells treated with NP(Se)s and cisplatin. Thereafter, patient-derived xenograft models of hepatic carcinoma (PDX) and multidrug-resistant lung cancer (PDX) were established to evaluate the therapeutic effect of NP(Se)s, and a significant antitumor effect was achieved on both models with NP(Se)s. Overall, this study provides a promising strategy to break the redox balance for maximizing the efficacy of platinum-based cancer therapy.
癌细胞中过度的氧化应激可诱导癌细胞死亡。化疗的抗癌活性和耐药性与肿瘤细胞的氧化还原状态密切相关。在此，基于最广泛使用的抗癌药物顺铂合成了五种亲脂性铂（IV）前药，其抗癌疗效和耐药性与细胞内氧化还原状态密切相关。随后，选择了一系列顺铂敏感和耐药细胞系以及三种患者来源的原发性卵巢癌细胞来筛选这些前药。为了验证氧化还原平衡的破坏是否可以与这些铂（IV）前药相结合，我们随后合成了一种主链中含有二硒键的聚合物，用于包裹最有效的前药以形成纳米颗粒（NP（Se）s）。NP（Se）s可以有效地打破氧化还原平衡，同时消耗谷胱甘肽并增加活性氧，从而与顺铂产生协同作用。此外，采用全基因组分析RNA测序来全面了解用NP（Se）s和顺铂处理的细胞中转录组的变化以及氧化还原相关途径的改变。此后，建立了患者来源的肝癌异种移植模型（PDX）和多药耐药肺癌异种移植模型（PDX）来评估NP（Se）s的治疗效果，NP（Se）s在这两种模型上均取得了显著的抗肿瘤效果。总体而言，本研究提供了一种有前景的策略，即打破氧化还原平衡以最大化铂类癌症治疗的疗效。
