Self-assembled thioether-bridged paclitaxel-dihydroartemisinin prodrug for amplified antitumor efficacy-based cancer ferroptotic-chemotherapy. (22nd March 2023)

• Record Type: Journal Article
• Authors: Zheng, Yifei; Qin, Chao; Li, Fei; Qi, Jingxin; Chu, Xinyu; Li, Hao; Shi, Ting; Yan, Zhen; Yang, Lei; Xin, Xiaofei; Liu, Lisha; Han, Xiaopeng; Yin, Lifang
• Is Part Of: Biomaterials science. Volume 11:Number 9(2023)
• Page Start: 3321
• Page End: 3334
• Publication Date: 2023-03-22
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/d2bm02032g
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : In this study, ROS-sensitive prodrug nanoassemblies composed of a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug was constructed. The nanoassemblies with enhanced ferroptotic-chemotherapy promoted tumor cell death. Abstract : Ferroptosis has been proposed as one form of iron-dependent cell death, overgeneration of high-toxicity hydroxyl radicals (˙OH) tumor sites via Fenton reactions induced cell membrane damage. However, the insufficient intracellular concentrations of both iron and H2 O2 limited the anticancer performance of ferroptosis. In this study, ROS-sensitive prodrug nanoassemblies composed of a PEG2000-ferrous compound and a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug were constructed, which fully tapped ex/endogenous iron, ferroptosis inducers, and chemotherapeutic agents. Following cellular uptake, the intracellular oxidizing environment accelerated the self-destruction of nanoassemblies and triggered drug release. In addition to the chemotherapeutic effect, the activated dihydroartemisinin was capable of acting as a toxic ˙OH amplifier via the reinforced Fenton reaction, simultaneously depleting intracellular GSH, as well as inducing glutathione peroxidase 4 inactivation, further enhancing ferroptosis-dependent cancer cell proliferation inhibition. Meanwhile, the ROS generation-inductive and cell cycle arrest effect from the paclitaxel augmented synergetic ferroptotic-chemotherapy of cancer. Thus, the prodrug integrating dihydroartemisinin with paclitaxel via a single thioether bond represents a potent nanoplatform to exert amplified ferroptotic-chemotherapy for improved anticancer efficacy.