ArticleAntioxidants (Basel, Switzerland)2026
Engineering a Redox-Responsive Bimolecular Prodrug for Targeted Gastric Cancer Combination Therapy: Design, Synthesis, and In Vivo Evaluation.
Article in Antioxidants (Basel, Switzerland), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Combination chemotherapy often suffers from asynchronous pharmacokinetics and off-target toxicity. To address this, we designed a novel, unreported engineered prodrug-a redox-responsive bimolecular prodrug (CA-4-Gefitinib)-by engineering a disulfide bond as a cleavable linker to covalently conjugate the tubulin inhibitor combretastatin A-4 (CA-4) and the EGFR inhibitor Gefitinib. This molecular-level prodrug design enables tumor-selective drug activation in high-glutathione environments. This prodrug exhibited enhanced cellular uptake and potent antiproliferative activity against SGC-7901 gastric cancer cells, with significantly improved selectivity over normal cells (safety index of 98). Mechanistically, this engineered prodrug disrupted microtubule polymerization, induced G2/M arrest, suppressed ERK signaling, and promoted apoptosis. The prodrug's pharmacokinetic profile showed prolonged circulation and reduced systemic exposure to free CA-4, indicating favorable biodistribution. In a murine xenograft model, this prodrug demonstrated superior antitumor efficacy and markedly reduced systemic toxicity compared to the combination of free drugs. Our work presents a rational prodrug design strategy-a redox-responsive drug-drug conjugate prodrug-that synchronizes drug delivery, enhances tumor targeting, and maximizes synergistic efficacy, offering a promising platform for advanced cancer combination therapy.
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