Author:
Liu Fan,Xiang Qinyanqiu,Luo Yuanli,Luo Ying,Luo Wenpei,Xie Qirong,Fan Jingdong,Ran Haitao,Wang Zhigang,Sun Yang
Abstract
Abstract
Background
Oxidative stress (OS) induced by an imbalance of oxidants and antioxidants is an important aspect in anticancer therapy, however, as an adaptive response, excessive glutathione (GSH) in the tumor microenvironment (TME) acts as an antioxidant against high reactive oxygen species (ROS) levels and prevents OS damage to maintain redox homoeostasis, suppressing the clinical efficacy of OS-induced anticancer therapies.
Results
A naturally occurring ROS-activating drug, galangin (GAL), is introduced into a Fenton-like catalyst (SiO2@MnO2) to form a TME stimulus-responsive hybrid nanopharmaceutical (SiO2-GAL@MnO2, denoted SG@M) for enhancing oxidative stress. Once exposed to TME, as MnO2 responds and consumes GSH, the released Mn2+ converts endogenous hydrogen peroxide (H2O2) into hydroxyl radicals (·OH), which together with the subsequent release of GAL from SiO2 increases ROS. The “overwhelming” ROS cause OS-mediated mitochondrial malfunction with a decrease in mitochondrial membrane potential (MMP), which releases cytochrome c from mitochondria, activates the Caspase 9/Caspase 3 apoptotic cascade pathway. Downregulation of JAK2 and STAT3 phosphorylation levels blocks the JAK2/STAT3 cell proliferation pathway, whereas downregulation of Cyclin B1 protein levels arrest the cell cycle in the G2/M phase. During 18 days of in vivo treatment observation, tumor growth inhibition was found to be 62.7%, inhibiting the progression of pancreatic cancer. Additionally, the O2 and Mn2+ released during this cascade catalytic effect improve ultrasound imaging (USI) and magnetic resonance imaging (MRI), respectively.
Conclusion
This hybrid nanopharmaceutical based on oxidative stress amplification provides a strategy for multifunctional integrated therapy of malignant tumors and image-visualized pharmaceutical delivery.
Graphical Abstract
Funder
National Natural Science Foundation of China
the Innovation Leaders Program of Chongqing Talents
Senior Medical Talents Program of Chongqing for Young and Middle-aged
Program for Youth Innovation in Future Medicine, Chongqing Medical University
Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University.
Publisher
Springer Science and Business Media LLC
Subject
Pharmaceutical Science,Applied Microbiology and Biotechnology,Biomedical Engineering,Molecular Medicine,Medicine (miscellaneous),Bioengineering
Cited by
2 articles.
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