Nanoparticles targeting OPN loaded with BY1 inhibits vascular restenosis by inducing FTH1-dependent ferroptosis in vascular smooth muscle cells

• Published in: Biomaterials 2024-09, Vol.309, p.122613, Article 122613
• Main Authors: Zhang, Yu, Zheng, Bo-yang, Zhang, Qian-fan, Zhao, Ya-nan, Yu, Qi-ming, Liu, Xin, Ding, Si-ying, Qian, Shuang-shuang, Wu, Han, Wu, Qian-yu, Zhang, Yu-han, Zheng, Lei, Zhang, Xin-hua, Zhang, Hao-feng, Hao, Yi-ming, Lu, Jing-chao, Wang, Lei, Wen, Jin-kun, Zheng, Bin
• Format: Article
• Language: English
• Subjects: Animals; Drug delivery; Ferritins; Ferroptosis; Ferroptosis - drug effects; FTH1; Humans; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nanoparticles; Nanoparticles - chemistry; Oxidoreductases - metabolism; Vascular restenosis; VSMCs
• ISSN: 0142-9612; 1878-5905; 1878-5905
• DOI: 10.1016/j.biomaterials.2024.122613

Vascular restenosis following angioplasty continues to pose a significant challenge. The heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], known for its anticancer activity, was utilized as the parent ring to conjugate with a non-steroidal anti-inflammatory drug, resulting in the creation of the spliced conjugated compound BY1. We found that BY1 induced ferroptosis in VSMCs as well as in neointima hyperplasia. Furthermore, ferroptosis inducers amplified BY1-induced cell death, while inhibitors mitigated it, indicating the contribution of ferroptosis to BY1-induced cell death. Additionally, we established that ferritin heavy chain1 (FTH1) played a pivotal role in BY1-induced ferroptosis, as evidenced by the fact that FTH1 overexpression abrogated BY1-induced ferroptosis, while FTH1 knockdown exacerbated it. Further study found that BY1 induced ferroptosis by enhancing the NCOA4-FTH1 interaction and increasing the amount of intracellular ferrous. We compared the effectiveness of various administration routes for BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and nanoparticles targeting OPN loaded with BY1 (TOP@MPDA@BY1) for targeting proliferated VSMCs, for prevention and treatment of the restenosis. Our results indicated that TOP@MPDA@BY1 was the most effective among the three administration routes, positioning BY1 as a highly promising candidate for the development of drug-eluting stents or treatments for restenosis. [Display omitted] •This study evaluated the efficacy of BY1, a derivative of TGIC, for addressing restenosis after angioplasty.•BY1 was found to induce ferroptosis in vascular smooth muscle cells, leading to a significant increase in intracellular iron.•Ferritin heavy chain1 (FTH1) plays a critical role in BY1-induced ferroptosis, with its expression level altering VSMC death.•TOP@MPDA@BY1 was the most effective in three delivery methods, highlighting its potential as a novel anti-restenosis drug.