Hebei Key Laboratory of Functional Polymers, Institute of Polymer Science and Engineering, School of Chemical Engineering, Hebei University of Technology, Tianjin 300130, P. R. China.
Mol Pharm. 2024 Nov 4;21(11):5854-5863. doi: 10.1021/acs.molpharmaceut.4c00883. Epub 2024 Oct 1.
Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu to DOX, while that is about 10 wt % for PDHB without Cu. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu depletes intracellular GSH and is reduced to Cu simultaneously, which reacts with local HO to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.
细胞内铜离子稳态已成为癌症治疗的一个有吸引力的靶点。在此，我们报告了一种 2,2'-联吡啶-4,4'-二甲酸（DPA）功能化聚谷氨酸衍生物（PDHB），由于侧挂 DPA 与 Cu 之间的强配位能力，它能够迅速形成 PDHB-铜配合物（PDHB@Cu）。由于 Cu 对阿霉素（DOX）的高亲和力，实现了 DOX 的高载药量（>30wt%），而没有 Cu 的 PDHB 的载药量约为 10wt%。所得的 PDHB@Cu-DOX 可以响应特定的内源性刺激（pH 和谷胱甘肽（GSH）），释放 Cu 和 DOX。释放的 DOX 直接破坏肿瘤细胞的 DNA 引起细胞凋亡，而 Cu 则耗尽细胞内 GSH 并同时被还原为 Cu，后者与局部 HO 反应通过芬顿样反应生成高毒性的·OH，从而实现协同化学动力学和化疗。本报告提供了一种有趣的聚合物离子载体策略，将足够的铜离子递送到癌细胞中，通过替换离子载体成分，也可以很容易地扩展到其他金属离子，因此在纳米医学中有广泛的应用。
