A Nanoscale Trans‐Platinum(II)‐Based Supramolecular Coordination Self‐Assembly with a Distinct Anticancer Mechanism

Abstract

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‐[PtCl₂(pyridine)(NH₃)] (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.