Chen Lu, Lin Zhenjie, Liu Lizhu, Zhang Xiuming, Shi Wei, Ge Dongtao, Sun Yanan
Key Laboratory of Biomedical Engineering of Fujian Province University/Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, College of Materials, Xiamen University, Xiamen 361005, China.
ACS Biomater Sci Eng. 2019 Sep 9;5(9):4861-4869. doi: 10.1021/acsbiomaterials.9b00461. Epub 2019 Aug 26.
Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Besides, advantages of polymeric nanomaterials in improving anticancer efficacy and reducing side effect are widely accepted. In this work, based on the property of polypodamine to chelate metal ions, ultrasmall poly(ethylene glycol)-modified polydopamine nanoparticles, (UPDA-PEG)@Fe nanoparticles, a novel ferroptosis agent, was rationally designed by chelating iron ions on ultrasmall polydopamine nanoparticles modified by PEG. This treatment led to a bigger specific surface area, which could support more reactive sites to chelate large number of iron ions, which is beneficial for exploring the detailed mechanism of ferroptosis-induced tumor cell death by iron ions. Also, the pH-dependent release of iron ions can reach approximately 70% at pH 5.0, providing the advantage of application in tumor microenvironment. The in vitro tests showed that the as-prepared NPs exhibit an effective anticancer effect on tumor cells including 4T1 and U87MG cells, yet ferric ions show a stronger ability of killing cancer cells than ferrous ions. Differences between ferrous ions and ferric ions in the ferroptosis pathway were monitored by the change of marker, including reactive oxygen species (ROS), glutathione peroxidase 4, and lipid peroxide (LPO), as well as the promoter and inhibitor of ferroptosis pathway. UPDA-PEG@Fe nanoparticles induce ferroptosis that depends more on ROS; however, a more LPO-dependent ferroptosis is induced by UPDA-PEG@Fe nanoparticles. Additionally, the in vivo studies using tumor-bearing Balb/c mice demonstrated that the as-prepared NPs could significantly inhibit tumor progression. UPDA-PEG@Fe nanoparticles reported herein represent the nanoparticles related to iron ions for chemotherapy against cancer through the ferroptosis pathway.
铁死亡作为一种很有前景的癌细胞杀伤机制，已成为癌症治疗领域的研究热点。此外，聚合物纳米材料在提高抗癌疗效和降低副作用方面的优势已被广泛认可。在本研究中，基于聚多巴胺螯合金属离子的特性，通过在聚乙二醇修饰的超小聚多巴胺纳米颗粒上螯合铁离子，合理设计了一种新型铁死亡诱导剂——超小聚（乙二醇）修饰的聚多巴胺纳米颗粒（UPDA-PEG）@Fe纳米颗粒。这种处理方式使比表面积更大，能够支持更多的活性位点螯合大量铁离子，这有利于探究铁离子诱导铁死亡导致肿瘤细胞死亡的详细机制。此外，铁离子在pH 5.0时的pH依赖性释放率可达约70%，这为其在肿瘤微环境中的应用提供了优势。体外试验表明，所制备的纳米颗粒对包括4T1和U87MG细胞在内的肿瘤细胞具有有效的抗癌作用，但三价铁离子比二价铁离子表现出更强的癌细胞杀伤能力。通过包括活性氧（ROS）、谷胱甘肽过氧化物酶4和脂质过氧化物（LPO）等标志物以及铁死亡途径的促进剂和抑制剂的变化，监测了二价铁离子和三价铁离子在铁死亡途径中的差异。UPDA-PEG@Fe纳米颗粒诱导的铁死亡更多地依赖于ROS；然而，UPDA-PEG@Fe纳米颗粒诱导的是一种更依赖LPO的铁死亡。此外，使用荷瘤Balb/c小鼠进行的体内研究表明，所制备的纳米颗粒能够显著抑制肿瘤进展。本文报道的UPDA-PEG@Fe纳米颗粒代表了通过铁死亡途径用于癌症化疗的与铁离子相关的纳米颗粒。
