Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy
Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy
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探讨硫/硒/碳键对用于癌症治疗的前药纳米组装体的影响
DOI：
10.1038/s41467-019-11193-x
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发表时间：
2019-07-19
影响因子：
16.6
通讯作者：
Sun, Jin
中科院分区：
文献类型：
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作者：
Sun, Bingjun;Luo, Cong;Sun, Jin
由于活性氧和谷胱甘肽的同时过量产生，肿瘤细胞呈现氧化还原异质性的细胞内微环境。合理设计氧化还原响应型药物递送系统是有效治疗癌症的良好前景。本论文以硫醚键、二硫键、硒醚键、二硒化键、碳键或碳-碳键为连接键，合成了6种紫杉醇-香茅醇结合物。这些前体药物可以自组装成具有超高载药量的均匀纳米颗粒。有趣的是，硫/硒/碳键显著影响前药纳米组装的效率。键角/二面角影响药物的自组装、稳定性和药代动力学。硫/硒/碳键的氧化还原响应性对药物释放和细胞毒性有显著影响。此外，硒醚/二硒化键具有独特的产生活性氧物种的能力，这进一步提高了这些前药的细胞毒性。我们的发现深入了解了化学键对前药纳米组装的影响，并为合理设计用于癌症治疗的氧化还原响应型药物输送系统提供了策略。
Tumor cells are characterized as redox-heterogeneous intracellular microenvironment due to the simultaneous overproduction of reactive oxygen species and glutathione. Rational design of redox-responsive drug delivery systems is a promising prospect for efficient cancer therapy. Herein, six paclitaxel-citronellol conjugates are synthesized using either thioether bond, disulfide bond, selenoether bond, diselenide bond, carbon bond or carbon-carbon bond as linkages. These prodrugs can self-assemble into uniform nanoparticles with ultrahigh drug-loading capacity. Interestingly, sulfur/selenium/carbon bonds significantly affect the efficiency of prodrug nanoassemblies. The bond angles/dihedral angles impact the self-assembly, stability and pharmacokinetics. The redox-responsivity of sulfur/selenium/carbon bonds has remarkable influence on drug release and cytotoxicity. Moreover, selenoether/diselenide bond possess unique ability to produce reactive oxygen species, which further improve the cytotoxicity of these prodrugs. Our findings give deep insight into the impact of chemical linkages on prodrug nanoassemblies and provide strategies to the rational design of redox-responsive drug delivery systems for cancer therapy.