Development of a Tumor Microenvironment‐Responsive Co(III)‐Chrysin Prodrug: Synthesis, Activation Profiling, and In Vitro Antineoplastic Evaluation

A drug masking strategy involves designing molecular systems that remain inactive until reaching the target site, where specific stimuli trigger activation, thereby minimizing off-target effects, reducing systemic toxicity, and enhancing therapeutic precision and efficacy. A cobalt(III)-chrysin prodrug (CCP) was designed to selectively release the anticancer flavonoid chrysin under reducing tumor conditions. Spectroscopic, cytotoxicity, and biomolecular studies demonstrate CCP's stability, controlled activation, and selective cytotoxicity. This work highlights CCP, a metal-drug conjugate, as an innovative targeted therapeutic strategy.

Chrysin, a bioactive flavonoid with significant anticancer potential, is limited by its nonspecific toxicity and poor targetability. To overcome these challenges, we developed a cobalt(III)-chrysin prodrug (CCP) designed for selective activation in the hypoxic and reducing tumor microenvironment. The CCP was synthesized and characterized using spectroscopic and analytical techniques, demonstrating stability under physiological conditions and controlled release of chrysin in reducing environments, as confirmed by HPLC, LC-MS, and ¹H NMR studies. Biomolecular interaction studies demonstrated its binding to BSA and ctDNA. In vitro cytotoxicity assays in HeLa cells revealed that CCP effectively masked chrysin's activity, exhibiting an IC₅₀ value > 100 µM compared to free chrysin (IC₅₀ = 15 ± 2 µM). The activation of CCP with sodium ascorbate reduced its IC₅₀, confirming its ability to release chrysin in a biologically relevant context. Live-dead assays validated the selective cytotoxicity of activated CCP, with increased cell death observed under reducing conditions. These findings highlight CCP as a promising prodrug system, combining the pharmacological benefits of chrysin with the advantages of metal-drug conjugates for hypoxia-activated cancer therapy.

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