Department of Radiology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, PR China.
School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, PR China.
Acta Biomater. 2022 Jan 15;138:518-527. doi: 10.1016/j.actbio.2021.11.007. Epub 2021 Nov 11.
As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (HO) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe)/gadolinium ions (Gd) via chelation reactions between Fe/Gd and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular HO, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd may serve as a contrast agent for tumor-specific T-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. STATEMENT OF SIGNIFICANCE: Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.
作为一种有前途的新型非凋亡性细胞死亡形式，铁死亡有望成为基于凋亡的癌症治疗的有效补充。然而，肿瘤中细胞内谷胱甘肽 (GSH) 水平较高和过氧化氢 (HO) 不足限制了铁死亡的疗效。在这里，我们通过螯合反应将两亲聚合物骨架 (P-SS-D)、肉桂醛前药 (CA-OH) 和铁离子 (Fe)/钆离子 (Gd) 纳入一种名为 FCS/GCS 的治疗诊断纳米平台。当在具有高 GSH 水平的肿瘤微环境中递送时，纳米颗粒会被 P-SS-D 的聚二硫键骨架解聚。激活的 CA 会消耗 GSH 并提高细胞内 HO，随后通过 Fenton 反应产生大量 •OH 水平。活性氧 (ROS) 的产生进一步加速 CA 的激活。二硫键、CA 和 Fe 的 GSH 消耗会下调 GPX4 并产生 •OH，从而加速脂质过氧化物 (LPO) 的积累，进而增强铁死亡。此外，释放的 Gd 可能可用作肿瘤特异性 T1 加权磁共振成像 (MRI) 的造影剂。因此，合理设计的 FCS/GCS 系统是一种很有前途的有效基于 MRI 的可视化铁死亡治疗策略。
