A "Ferroptosis-Amplifier" Hydrogel for Eliminating Refractory Cancer Stem Cells Post-lumpectomy.

Abstract

The unique "Iron Addiction" feature of cancer stem cells (CSCs) with tumorigenicity and plasticity generally contributes to the tumor recurrence and metastasis after a lumpectomy. Herein, a novel "Ferroptosis Amplification" strategy is developed based on integrating gallic acid-modified FeOOH (GFP) and gallocyanine into Pluronic F-127 (F127) and carboxylated chitosan (CC)-based hydrogel for CSCs eradication. This "Ferroptosis Amplifier" hydrogel is thermally sensitive and achieves rapid gelation at the postsurgical wound in a breast tumor model. Specifically, gallocyanine, as the Dickkopf-1 (DKK1) inhibitor, can decrease the expression of SLC7A11 and GPX4 and synergistically induce ferroptosis of CSCs with GFP. Encouragingly, it is found that this combination suppresses the migratory and invasive capability of cancer cells <i>via</i> the downregulation of matrix metalloproteinase 7 (MMP7). The <i>in vivo</i> results further confirm that this "Ferroptosis Amplification" strategy is efficient in preventing tumor relapse and lung metastasis, manifesting an effective and promising postsurgical treatment for breast cancer.