Combination therapy to overcome ferroptosis resistance by biomimetic self-assembly nano-prodrug

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Asian Journal of Pharmaceutical Sciences Pub Date : 2023-09-01 DOI:10.1016/j.ajps.2023.100844
Yong Huang , Yi Lin , Bowen Li , Fu Zhang , Chenyue Zhan , Xin Xie , Zhuo Yao , Chongzhi Wu , Yuan Ping , Jianliang Shen
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Abstract

Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer. Herein, we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib (Gefi), ferrocene (Fc) and dihydroartemisinin (DHA) for the combined therapy of both ferroptosis and apoptosis. In the tumor microenvironment, this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH. Interestingly, the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc, further executing tumor cell death with concomitant chemotherapy by Gefi. More importantly, this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis, as well as no noticeable side-effects during treatments. This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.

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仿生自组装纳米前药联合治疗抗脱铁性
铁凋亡已成为一种有效的非凋亡细胞死亡形式,为避免细胞凋亡途径的化疗耐药提供了一种有希望的选择,并作为癌症的易感性。在此,我们构建了一个仿生自组装纳米前药系统,该系统能够共同递送吉非替尼(Gefi)、二茂铁(Fc)和双氢青蒿素(DHA),用于铁死亡和细胞凋亡的联合治疗。在肿瘤微环境中,这种纳米前药能够在高水平谷胱甘肽的作用下分解并触发药物释放。有趣的是,释放的DHA可以下调GPX4水平,增强Fc的细胞内铁凋亡,进一步导致肿瘤细胞死亡并伴有Gefi化疗。更重要的是,该纳米前药通过包覆相关细胞膜,具有高度同源的靶向能力,对肿瘤生长和转移具有明显的抑制作用,且在治疗过程中无明显的副作用。这种简单的小分子自组装纳米前药为铁中毒联合化疗提供了一种合理设计的新模式。
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来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
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