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A Dual Stimuli-responsive Nanoplatform Loaded Pt IV -triptolide Prodrug for Achieving Synergistic Therapy Toward Breast Cancer.

Kang FangYanting SunJingxian YangXiaochun HuMengyao ChenRuihao LiXinda YangTing FanJunjie WuXiaohan TongChunyan DongShuo Shi
Published in: Advanced healthcare materials (2023)
To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide, Herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy both "1+1″ apoptosis and "1+1″ ferroptosis is designed. Remarkably, ZIF8 in response to tumor microenvironment enhances drug targeting and protects drugs from premature degradation. Meanwhile, Pt IV  center can be easily reduced to cisplatin because of the large amount of GSH, thus liberating the triptolide as coordinated ligand. The released cisplatin and hemin in turn boost the tumor cell ″1+1″ apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction through Pt IV  weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus ″1+1″ ferroptosis could be achieved. Both in vitro and in vivo results demonstrated that the nanosystem could not only perform superior specificity and therapeutic outcomes, but also reduce the toxicity to normal cells/ tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provided an efficient therapeutic strategy for cancer treatment by virtue of the synergistic effect of enhanced "1+1″ apoptosis and "1+1″ ferroptosis therapies. This article is protected by copyright. All rights reserved.
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