A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis

作者：Luo, Shiwei; Ma, Di; Wei, Ruili; Yao, Wang; Pang, Xinrui; Wang, Ye; Xu, Xiangdong; Wei, Xinhua; Guo, Yuan; Jiang, Xinqing^*; Yuan, Youyong^*; Yang, Ruimeng^*

来源：Acta Biomaterialia, 2022, 138: 518-527.

DOI：10.1016/j.actbio.2021.11.007

• Ferroptosis
• Chelation
• Fenton reaction
• T-1-weighted magnetic resonance imaging

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 (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we de-signed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ 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 H2O2, followed by a high level of Fenton reaction to gen-erate abundant center dot OH levels. The generation of reactive oxygen species (ROS) further accelerates CA acti-vation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates center dot OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T-1-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 sup-plement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by exces-sive 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.