OPN-modified nanoparticles loading BY1 inhibits vascular restenosis by inducing FTH1-dependent ferroptosis in vascular smooth muscle cells

Abstract

Abstract Percutaneous coronary intervention has greatly improved the quality of life in patients with coronary artery disease. However, the vascular restenosis after angioplasty remains a challenging problem. Thus, there is still an urgent need to rationally design more effective drug and drug delivery system. In this study, the heterocyclic trioxirane compound [1, 3, 5-tris((oxiran-2-yl)methyl)-1, 3, 5-triazinane-2, 4, 6-trione (TGIC)], which has an anticancer activity, was used as the parent ring to conjugate with non-steroidal anti-inflammatory drug to obtain the spliced conjugated compound BY1, which is expected to prevent vascular remodeling. We found that BY1 potently induced ferroptosis in the cultured VSMCs as well as in neointima hyperplasia, accompanied by the significant accumulation of reactive oxygen species (ROS) and intracellular iron. The ferroptosis inducer and inhibitor enhanced and rescued, respectively, BY1-induced cell death, indicating that ferroptosis contributes to BY1-induced cell death in VSMCs. Further, we demonstrated that ferritin heavy chain1 (FTH1) was a key determinant for BY1-induced VSMC ferroptosis, as evidenced by the observations that FTH1 overexpression abrogated, while knockdown of FTH1 exacerbated, BY1-induced VSMC ferroptosis. Meanwhile, we compared the efficacy of different administration routes of BY1, including BY1-coated balloons, hydrogel-based BY1 delivery, and Osteopontin (OPN)-modified nanoparticles loading BY1 for targeting proliferated VSMCs (BY1-NP-OPN), for prevention and treatment of the restenosis. Our results suggest that BY1-NP-OPN is the most effective among the three administration routes, supporting the notion that BY1 might serve as a promising candidate for the development of drug coated stents or anti-restenosis drug.