Breaking the Intracellular Redox Balance with Diselenium Nanoparticles for Maximizing Chemotherapy Efficacy on Patient-Derived Xenograft Models
Breaking the Intracellular Redox Balance with Diselenium Nanoparticles for Maximizing Chemotherapy Efficacy on Patient-Derived Xenograft Models
复制标题
用二硒纳米颗粒打破细胞内氧化还原平衡，最大限度地提高患者异种移植模型的化疗效果
DOI：
10.1021/acsnano.0c06190
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发表时间：
2020-12-22
期刊：
影响因子：
17.1
通讯作者：
Xiao, Haihua
中科院分区：
文献类型：
--
作者：
Wei, Dengshuai;Yu, Yingjie;Xiao, Haihua
癌细胞中过度的氧化应激会导致癌细胞死亡。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。本论文以目前应用最广泛的抗癌药物顺铂为基础，合成了5种亲脂性铂(IV)前体药，其抗癌效果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个患者来源的原代卵巢癌细胞来筛选这些前体药物。为了验证氧化还原平衡的破坏是否可以与这些铂(IV)前药结合，我们合成了主链上带有二硒键的聚合物，用于包裹最有效的前药形成纳米粒子(Np(Se)S)。NP(Se)S可通过同时消耗GSH和增加ROS来有效地打破氧化还原平衡，从而与顺铂达到协同作用。此外，通过rna-seq的全基因组分析提供了对NP(Se)S和顺铂处理的细胞的转录组的变化和氧化还原相关通路的改变的全面了解。在此基础上，建立了人肝癌和多药耐药肺癌患者来源的异种移植模型，以评价NP(Se)S的治疗效果，并用Np(Se)S对这两种肿瘤模型都取得了显著的抗肿瘤作用。
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 nano- particles (NP(Se)s). NP(Se)s can efficiently break the redox balance via simultaneously depleting GSH and augmenting ROS, thereby achieving a synergistic effect with cisplatin. In addition, genome-wide analysis via 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 (PDXHCC) and multidrug-resistant lung cancer (PDXMDR) 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.