Fe3+-binding transferrin nanovesicles encapsulating sorafenib induce ferroptosis in hepatocellular carcinoma.

IF 11.3 1区 医学 Q1 Medicine Biomaterials Research Pub Date : 2023-07-01 DOI:10.1186/s40824-023-00401-x
Youmei Xiao, Zhanxue Xu, Yuan Cheng, Rufan Huang, Yuan Xie, Hsiang-I Tsai, Hualian Zha, Lifang Xi, Kai Wang, Xiaoli Cheng, Yanfeng Gao, Changhua Zhang, Fang Cheng, Hongbo Chen
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引用次数: 2

Abstract

Background: Ferroptosis, iron-dependent cell death, is an established mechanism for cancer suppression, particularly in hepatocellular carcinoma (HCC). Sorafenib (SOR), a frontline drug for the treatment of HCC, induces ferroptosis by inhibiting the Solute Carrier family 7 member 11 (SLC7A11), with inadequate ferroptosis notably contributing to SOR resistance in tumor cells.

Methods: To further verify the biological targets associated with ferroptosis in HCC, an analysis of the Cancer Genome Atlas (TCGA) database was performed to find a significant co-upregulation of SLC7A11 and transferrin receptor (TFRC), Herein, cell membrane-derived transferrin nanovesicles (TF NVs) coupled with Fe3+ and encapsulated SOR (SOR@TF-Fe3+ NVs) were established to synergistically promote ferroptosis, which promoted the iron transport metabolism by TFRC/TF-Fe3+ and enhanced SOR efficacy by inhibiting the SLC7A11.

Results: In vivo and in vitro experiments revealed that SOR@TF-Fe3+ NVs predominantly accumulate in the liver, and specifically targeted HCC cells overexpressing TFRC. Various tests demonstrated SOR@TF-Fe3+ NVs accelerated Fe3+ absorption and transformation in HCC cells. Importantly, SOR@TF-Fe3+ NVs were more effective in promoting the accumulation of lipid peroxides (LPO), inhibiting tumor proliferation, and prolonging survival rates in HCC mouse model than SOR and TF- Fe3+ NVs alone.

Conclusions: The present work provides a promising therapeutic strategy for the targeted treatment of HCC.

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包裹索拉非尼的Fe3+结合转铁蛋白纳米囊泡诱导肝癌铁凋亡。
背景:铁依赖性细胞死亡(Ferroptosis)是一种已知的肿瘤抑制机制,特别是在肝细胞癌(HCC)中。索拉非尼(Sorafenib, SOR)是治疗HCC的一线药物,通过抑制溶质载体家族7成员11 (SLC7A11)诱导铁下垂,而铁下垂不足是导致肿瘤细胞SOR耐药的重要原因。方法:为了进一步验证HCC中与铁死亡相关的生物学靶点,我们对癌症基因组图谱(TCGA)数据库进行了分析,发现SLC7A11和转铁蛋白受体(TFRC)存在显著的共上调。在此,我们建立了细胞膜源性转铁蛋白纳米囊泡(TF NVs)与Fe3+和封装的SOR (SOR@TF-Fe3+ NVs)结合,协同促进铁死亡。通过TFRC/TF-Fe3+促进铁转运代谢,并通过抑制SLC7A11增强SOR的功效。结果:体内和体外实验显示SOR@TF-Fe3+ NVs主要聚集在肝脏中,并特异性靶向过表达TFRC的HCC细胞。各种试验表明SOR@TF-Fe3+ NVs加速了肝癌细胞对Fe3+的吸收和转化。重要的是,在HCC小鼠模型中,SOR@TF-Fe3+ NVs在促进脂质过氧化物(LPO)积累、抑制肿瘤增殖和延长生存率方面比单独使用SOR和TF-Fe3+ NVs更有效。结论:本研究为肝癌的靶向治疗提供了一种有前景的治疗策略。
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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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