Bio-reductive hetero-bimetallic Co(III)-Pt(II) complex for tumor-selective platinum release and cytotoxicity

Abstract

The application of bioreductive metalloprodrugs in cancer therapy has emerged as a promising strategy to achieve site-specific activation of cytotoxic agents by exploiting the reductive microenvironment which is a characteristic of tumors, thereby minimizing off-target effects. In this study, we report the synthesis of a heterobimetallic [Co(III)-Pt(II)] complex designed to harness the tumor-specific redox conditions for selective anticancer activity. The complex was thoroughly characterized using a suite of spectroscopic techniques, and its redox behavior was investigated via electrochemical analysis, which revealed a quasi-reversible one-electron reduction with an E₁/₂ value of -0.52 V vs Ag/AgCl—suggesting the feasible reduction of Co(III) under biologically relevant conditions. Cellular uptake studies, performed using inductively coupled plasma mass spectrometry (ICP-MS), demonstrated efficient internalization of the complex within 12 hours in A549 lung carcinoma cells. Furthermore, binding studies with 5′-guanosine monophosphate (5′-GMP), conducted via electrospray ionization mass spectrometry (ESI-MS), confirmed the reductive release of the Pt(II) fragment and its subsequent coordination with nucleophilic targets. Induction of apoptosis was verified using Annexin V assays, indicating the activation of programmed cell death pathways.The complex exhibited potent cytotoxicity under both normoxic and hypoxic conditions in A549 cells and showed significant activity against a panel of cancer cell lines, including HT-29 (colorectal), MCF-7 (breast), and MDA-MB-231, a highly aggressive triple-negative breast cancer line. These findings highlight the potential of this redox-responsive bimetallic complex as a next-generation anticancer agent capable of overcoming platinum resistance, enhancing tumor selectivity, and reducing systemic toxicity relative to conventional platinum-based therapies.