Researchers from the Chinese Academy of Sciences developed a coordination nanomedicine (ZnDHT NM) designed for cascade-specific Fe3+ capture and in situ catalysis. The approach utilizes 2,5-dihydroxyterephthalic acid (DHT) complexed with Zn2+ to induce tumor cell death. The study was published in Science China Press.
Tumor metastasis, recurrence, and therapeutic resistance are primary challenges in clinical cancer treatment. The presence of cancer stem-like cells (CSCs), which exhibit stem cell-like properties, is a significant factor contributing to these issues.
Current treatment strategies targeting CSCs using conventional drugs face limitations, including insufficient tumor-specific cytotoxicity and low in vivo efficiency in suppressing CSC stemness. This allows residual tumor cells to undergo epithelial-to-mesenchymal transition (EMT) and revert to CSC-like states.
While some combination therapies have demonstrated effectiveness in targeting both tumor cells and CSCs, their complexity and potential side effects present challenges for clinical application. There is a need for novel therapeutic approaches capable of simultaneously inducing CSC differentiation and eliminating tumor cells.
Dr. Yufang Zhu, Dr. Chengtie Wu, and Dr. Jianlin Shi from the Shanghai Institute of Ceramics, Chinese Academy of Sciences, investigated these challenges.
Performance tests and theoretical calculations indicated that ZnDHT NM can selectively capture Fe3+, facilitating the catalytic generation of reactive oxygen species (ROS) by forming a hexacoordinated Fe-DHT complex with enhanced reducibility. Additionally, due to the higher affinity of DHT molecules for Fe3+ than other metal ions, Zn2+ is released from the nanomedicine structure.
ZnDHT NM suppresses EMT and depletes Fe3+ in the tumor microenvironment while promoting CSC differentiation and intracellular ROS production by inhibiting the Wnt signaling pathway and activating FoxO3. Concurrently, the release of Zn2+ inhibits glutathione reductase (GR), reducing glutathione (GSH) levels in tumor cells. The combination of selective ROS generation and redox imbalance induces apoptosis and ferroptosis in tumor cells.
In vivo experiments demonstrated that ZnDHT NM effectively inhibited the growth of orthotopic triple-negative breast tumors and prevented tumor metastasis and postoperative recurrence.
This study presents an innovative perspective of establishing biosafe nanomedicines to evoke effective therapeutic mechanisms against CSCs and bulk tumor cells concurrently by modulating endogenous substances, which is highly encouraging for cancer nanomedicine design and future tumor therapeutics.
Dr. Yufang Zhu, Shanghai Institute of Ceramics, Chinese Academy of Sciences
Journal Reference:
Chen, J., et al. (2025) Cascade specific endogenous Fe3+ interference and in situ catalysis for tumor therapy with stemness suppression. National Science Review. doi.org/10.1093/nsr/nwae434
