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Breakthroughs Made in Hypoxic Tumor Treatment by Prof. Hao Yongqiang’s Team

December 01, 2020      Author:

On November 17th, the research team led by Professor Hao Yongqiang from Shanghai Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine had their findings, titled "Activatable nanomedicine for overcoming hypoxia-induced resistance to chemotherapy and inhibiting tumor growth by inducing collaborative apoptosis and ferroptosis in solid tumor", published in Biomaterials, a high-impact journal. The first author of this paper is Fu Jingke, associate researcher from the Department of Orthopaedics.

Malignant solid tumor is characterized by hypoxia, which is closely related with angiogenesis, metastasis and drug resistance of tumor. Given that malignant solid tumor is easily recurrent and insensitive to radiotherapy and chemotherapy, Professor Hao's team have developed a nanomedicine that releases abundant oxygen to address the "bottlenecks" in clinical practice, thus providing a new method for the improvement of the hypoxic tumor-microenvironment and the chemotherapy of drug resistance of solid tumors.

Hypoxia has been firmly correlated to the drug resistance of solid tumors. Alleviation of hypoxia by tumor reoxygenation is expected to sensitize the chemotherapy toward solid tumors. Alternatively, ferroptosis provides a therapeutic strategy to overcome apoptotic resistance and multidrug resistance of solid tumors, collaboratively strengthening the chemotherapy toward hypoxic tumors. Herein, an ultrasound (US)-activatable nanomedicine was developed for overcoming hypoxia-induced resistance to chemotherapy and efficiently inhibiting tumor growth by inducing sensitized apoptosis and collaborative ferroptosis of tumor cells. This nanomedicine was constructed by integrating ferrate and doxorubicin into biocompatible hollow mesoporous silica nanoplatforms, followed by assembling a solid-liquid phase-change material of n-heneicosane. The US-induced mild hyperthermia initiates the phase change of n-heneicosane, enabling US-activated co-release of ferrate and doxorubicin. Results reveal that the released ferrate effectively reacts with water as well as the over-expressed hydrogen peroxide and glutathione in tumor cells, achieving tumor-microenvironment-independent reoxygenation and glutathione-depletion in tumors. The reoxygenation down-regulates expressions of hypoxia-inducible factor 1α and multidrug resistance gene/transporter P-glycoprotein in tumor cells, sensitizing the apoptosis-based doxorubicin chemotherapy. More importantly, exogenous iron metabolism from the nanomedicine initiates intracellular Fenton reactions, leading to reactive oxygen species overproduction and iron-dependent ferroptotic death of tumor cells. Furthermore, the glutathione-depletion inactivates the glutathione peroxidase 4 (GPX4, a critical regulatory target in ferroptosis), inhibiting the reduction of lipid peroxides and reinforcing the ferroptotic cell death. The sensitized chemotherapy together with the iron-dependent ferroptosis of tumor cells play a synergistic role in boosting the growth suppression of hypoxic osteosarcoma in vivo. Additionally, the nanomedicine acts as a nanoprobe for in vivo photoacoustic imaging and glutathione tracking, showing great potential as theranostic agents for hypoxic solid tumors treatment.


Author: Wu Shuangshuang

Affiliation: Shanghai Ninth People's Hospital

Translated by Zhang Wenying

Proofread by Xiao Yangning