A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer
A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer
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DOI：
10.1021/acsnano.3c01792
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发表时间：
2023-06-15
期刊：
影响因子：
17.1
通讯作者：
Xie, Zhigang
中科院分区：
文献类型：
--
作者：
Hao, Dengyuan;Meng, Qian;Xie, Zhigang
调节铜的含量对癌症和神经退行性疾病的治疗具有重要意义。本研究通过二硫键将紫杉醇（PTX）与铜螯合剂偶联，合成了aredox-responsive paclitaxel （PTX）前药。制备的前药（PSPA）对铜离子具有特异性螯合作用，并可与二硬脂酰磷酸乙醇胺-聚乙二醇（2000）在水介质中组装形成稳定的纳米颗粒（PSPA NPs）。PSPA NPs被肿瘤细胞内化后，可以对细胞内高水平的氧化还原活性物质做出反应，并有效释放PTX。铜螯合剂可通过细胞内铜耗竭增加氧化应激和异常代谢诱导的细胞死亡。化疗联合铜耗尽疗法对三阴性乳腺癌的治疗效果增强，且全身毒性可忽略不计。我们的工作可能为结合代谢调节和化疗来对抗恶性肿瘤提供新的见解。
Tuning the content of copper is of great significancefor the treatmentof cancer and neurodegenerative diseases. Herein, we synthesized aredox-responsive paclitaxel (PTX) prodrug by conjugating PTX witha copper chelator through a disulfide bond. The as-fabricated prodrug(PSPA) showed specific chelation toward copper ions and could assemblewith distearoyl phosphoethanolamine-PEG(2000) to form stablenanoparticles (PSPA NPs) in aqueous media. Upon being internalizedby tumor cells, PSPA NPs could respond to high levels of redox-activespecies inside cells and efficiently release PTX. The copper chelatorcould increase oxidative stress- and abnormal metabolism-induced celldeath through intracellular copper depletion. The combination of chemotherapyand copper depletion therapy generated an enhanced therapeutic outcometoward triple-negative breast cancer with an ignorable systemic toxicity.Our work may provide insight into the combination of metabolic regulationand chemotherapy for combating malignant tumors.