Hao Dengyuan, Meng Qian, Li Chaonan, Lu Shaojin, Xiang Xiujuan, Pei Qing, Jing Xiabin, Xie Zhigang
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, People's Republic of China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, People's Republic of China.
ACS Nano. 2023 Jul 11;17(13):12383-12393. doi: 10.1021/acsnano.3c01792. Epub 2023 Jun 15.
Tuning the content of copper is of great significance for the treatment of cancer and neurodegenerative diseases. Herein, we synthesized a redox-responsive paclitaxel (PTX) prodrug by conjugating PTX with a copper chelator through a disulfide bond. The as-fabricated prodrug (PSPA) showed specific chelation toward copper ions and could assemble with distearoyl phosphoethanolamine-PEG to form stable nanoparticles (PSPA NPs) in aqueous media. Upon being internalized by tumor cells, PSPA NPs could respond to high levels of redox-active species inside cells and efficiently release PTX. The copper chelator could increase oxidative stress- and abnormal metabolism-induced cell death through intracellular copper depletion. The combination of chemotherapy and copper depletion therapy generated an enhanced therapeutic outcome toward triple-negative breast cancer with an ignorable systemic toxicity. Our work may provide insight into the combination of metabolic regulation and chemotherapy for combating malignant tumors.
调节铜的含量对于癌症和神经退行性疾病的治疗具有重要意义。在此，我们通过二硫键将紫杉醇（PTX）与铜螯合剂偶联，合成了一种氧化还原响应型紫杉醇前药。所制备的前药（PSPA）对铜离子具有特异性螯合作用，并能与二硬脂酰磷脂酰乙醇胺-聚乙二醇组装形成稳定的纳米颗粒（PSPA NPs）。PSPA NPs被肿瘤细胞内化后，可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。化疗与铜耗竭疗法的联合应用对三阴性乳腺癌产生了增强的治疗效果，且全身毒性可忽略不计。我们的工作可能为代谢调节与化疗联合对抗恶性肿瘤提供思路。
