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To address this, we designed a novel, unreported engineered prodrug\u2014a redox-responsive bimolecular prodrug (CA-4-Gefitinib)\u2014by 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\u2019s 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\u2014a redox-responsive drug\u2013drug conjugate prodrug\u2014that synchronizes drug delivery, enhances tumor targeting, and maximizes synergistic efficacy, offering a promising platform for advanced cancer combination therapy.<\/jats:p>","DOI":"10.3390\/antiox15091214","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:09Z","timestamp":1789999929000},"page":"1214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering a Redox-Responsive Bimolecular Prodrug for Targeted Gastric Cancer Combination Therapy: Design, Synthesis, and In Vivo Evaluation"],"prefix":"10.3390","volume":"15","author":[{"given":"Chao","family":"Wang","sequence":"first","affiliation":[{"name":"Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China"},{"name":"Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Yutao","family":"Xiu","sequence":"additional","affiliation":[{"name":"Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China"},{"name":"Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Yujing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China"},{"name":"Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Jiazhen","family":"Xu","sequence":"additional","affiliation":[{"name":"Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China"},{"name":"Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Yanhong","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Nursing, Qingdao Binhai University, Qingdao 266555, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-0440","authenticated-orcid":false,"given":"Dongming","family":"Xing","sequence":"additional","affiliation":[{"name":"Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China"},{"name":"Qingdao Cancer Institute, Qingdao University, Qingdao 266071, China"},{"name":"School of Life Sciences, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.addr.2015.10.022","article-title":"Recent advances of cocktail chemotherapy by combination drug delivery systems","volume":"98","author":"Hu","year":"2016","journal-title":"Adv. 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