Authors
Cuiman Tang, Zhongjuan Wang, Yankun Liu, Zhicun Liu, Wen Zhu, Xiuhua Zhao
Published in
ACS nano. Jul 21, 2026. Epub Jul 21, 2026.
Abstract
Selenium deficiency is linked to gastric cancer, and p53 mutant tumors often acquire chemoresistance. To address this, we designed a camptothecin (CPT) dimeric prodrug with a hybrid -S-Se-S- linker (CPT-S-Se-S-CPT). It self-assembles into uniform nanoparticles (SSeSCPT NPs) with dual redox-responsive release triggered by glutathione and reactive oxygen species. Selenium plays dual synergistic roles: it enhances cellular uptake and pharmacokinetics while reducing systemic toxicity; it also acts as a redox-active center to amplify oxidative stress, activating p38/MAPK and unfolded protein response pathways, thereby inducing p53-independent apoptosis and overcoming drug resistance. In vivo, SSeSCPT NPs prolong plasma half-life, achieve efficient tumor accumulation via the EPR effect, and show potent antitumor activity in p53 mutant gastric cancer models. Surface selenium groups recognize Toll-like receptor 4 (TLR4) overexpressed on tumor cells, promoting clathrin/caveolin-mediated endocytosis and bypassing EPR size limitations. This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy. It also reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks. This work provides mechanistic insights and translational directions for precision therapy of p53 mutant gastrointestinal malignancies.
PMID:
42478957
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.
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