Lipophilic Integrated Bioorthogonal Self-Catalyzed Nitric Oxide Donor–Platinum(IV) Prodrugs for Enhanced Antitumor Efficacy Against Esophageal Cancer

Esophageal cancer (EC) represents a globally prevalent malignancy with limited validated therapeutic targets, for which the cisplatin (CDDP)/5-fluorouracil (5-FU) combination remains the standard chemotherapy backbone. Nitric oxide (NO) and platinum(IV) complexes have attracted significant research interest in antitumor therapy. Previously designed integrated prodrugs suffered from poor cellular uptake. Herein, we reported the design, synthesis, and biological evaluation of a series of novel lipophilic integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs, in which cytoplasmic reductants catalyze the release of Pt(Ⅱ) and NO to produce synergistic antitumor effects in cancer cells. In vitro biological studies revealed that 10k exhibited 1.3- to 4.4-fold lower IC₅₀ values than CDDP against esophageal cancer cell lines, correlating with significantly enhanced lipophilicity. The lipophilic modification at the axial position of complex 10k significantly enhanced cellular Pt accumulation and DNA platination in KYSE-520 cells by 10.4- and 4.7-fold, respectively, compared to CDDP. The preferred complex 10k demonstrated favorable stability and pharmacokinetic properties. Compared with CDDP, 10k exhibited potent in vivo anti-esophageal cancer effects (71.1% tumor growth inhibition (TGI) against the KYSE-520 xenograft model) as well as inhibited lung metastasis, without significant systemic toxicity. Overall, the integrated prodrug 10k represents a promising candidate for EC treatment and deserves further in-depth studies.