Key Laboratory of Polymer Ecomaterials, Jilin Biomedical Polymers Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, P. R. China.
Adv Mater. 2024 May;36(19):e2312488. doi: 10.1002/adma.202312488. Epub 2024 Feb 8.
Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl(pyridine)(NH)] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.
耐药性显著阻碍了现有基于铂类抗癌药物的临床应用。新的铂类药物具有独特的作用机制，非常适合治疗铂类耐药性癌症。本文通过使用反式-[PtCl(pyridine)(NH)]（反式顺铂）、四羧基卟啉（TCPP）和苯甲酸（BA）作为构建块，制备了纳米级顺铂（II）基超分子配位自组装（Pt-TCPP-BA），以克服基于铂的化疗中的耐药性。机制研究表明，Pt-TCPP-BA 表现出对过氧化氢的响应性解离行为，同时生成生物活性的反式-Pt（II）和 TCPP-Pt 物种。与顺铂不同，这些降解产物通过链间交联和小沟结合与 DNA 相互作用，并诱导顺铂耐药癌细胞中细胞死亡相关蛋白（如 p53、裂解的 caspase 3、p21 和磷酸化 H2A 组蛋白家族成员 X）的显著上调。因此，Pt-TCPP-BA 在体外和体内对铂类耐药肿瘤均表现出强大的杀伤作用。总的来说，这项工作不仅为治疗耐药性癌症提供了一种新的铂类药物，还为基于铂的超分子抗癌药物的开发提供了一个新的范例。
