Old dogs may not learn new tricks, but old drugs do, according to a research team in China. The collaboration showed that Metformin, a small molecule drug that has been used for more than 50 years to treat type II diabetes, improves efficiency and efficacy of antibacterial treatments for rapid wound healing in mice.
They published their results on May 19 in Nano-research. (DOI 10.1007/s12274-022-4457-5)
The misuse of antibiotics has led to severe bacterial resistance, with about 1.27 million deaths in 2019 due to multidrug-resistant bacterial infections. Bacterial resistance poses a deadly threat to human health. Non-antibiotic antibacterial technologies and antibacterial nanoagents with specific catalytic activities not only produce toxic substrates to directly kill bacteria -; including antibiotic-resistant bacteria -; but may also reduce the risk of the bacteria developing drug resistance.”
Linlin Li, professor, co-corresponding author, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences
According to Li, chemodynamic therapy has attracted a lot of attention since it was developed in 2016 as a potential companion for cancer therapies, bacterial inactivation and infectious disease treatments. The therapy uses nanomaterials containing transition metals that react with hydrogen peroxide to produce a hydroxyl radical, which weakens and kills diseased or infected cells, making them more susceptible to immediate treatment.
“The reaction generates a toxic hydroxyl radical, which destroys the cell surface structure and causes the cell to leak its internal components,” Li said. “The nano-agents only catalyze the formation of hydroxyl radical at the site of tumor or inflamed tissue, so the therapy is highly specific to reduce off-target toxicity. Bacterial infections are also often associated with microenvironmental changes favorable to chemodynamic therapy.” .”
The researchers wanted to improve the antibacterial power of a nanodrug while reducing its toxicity to healthy cells -; a risk that can be difficult to manage due to the invasive nature of the infection.
“Positively charged moieties, such as quaternary ammonium salts and chitosan, have intrinsic antibacterial effects by adsorbing on the cell wall of bacteria, creating a compartment resistance effect and, finally, causing bacterial death,” Li said. “Metformin is a positively charged small molecule drug with reported anticancer, immunomodulatory and antibacterial effects. We speculated that integrating metformin with a chemodynamic therapy nanoagent would enhance its antibacterial effect.”
The researchers stirred metformin with copper chloride to form nanosheets whose surface was covered by the metformin molecules -; enhancing the positive charge of the nanoagent and enhancing its antibacterial effects, Li said.
In vitro tests revealed a biocompatible nanoplatform with better dispersity than a nanoagent without metformin, and higher antibacterial activity.
“Compared to previous reports where metformin was used alone as an antibacterial agent, in our experiments, excellent antimicrobial effects were achieved with lower concentrations of the nanosheets with a very short action time,” said Li, noting that they also studied the effects of metformin in other biomedical applications. applications to develop more therapies.
To further test the metformin-capped nanosheets, the researchers set up a model of staph infection in the skin of mice. The mice were divided into five groups, each of which received a variety of treatment. The group that received both the metformin nanosheets and additional hydrogen peroxide to promote hydroxyl radical production had the fastest wound healing, with complete closure by day 12 of treatment.
“This work not only develops an efficient nanoagent for chemodynamic therapy as an alternative antibacterial agent for treating skin wound infections, but it also provides ideas for discovering new uses for old drugs,” Li said.
Li is also affiliated with the Center on Nanoenergy Research, School of Physical Science and Technology, Guangxi University, and the School of Nanoscience and Technology, University of CAS. Other contributors include Xueyu Wang, Teng Xu, and co-corresponding author Shu Yan, 306th Clinical College of PLA, The Fifth Clinical College, Anhui Medical University; Shaobo Wang, Shuncheng Yao, Yunchao Zhao, Zeyu Zhang and Tian Huang, Beijing Institute of Nanoenergy and Nanosystems, CAS; Xueyu Wang and Jiao Gao, PLA Strategic Support Force Characteristic Medical Center. Xueyu Wang and Xu are also affiliated with the Beijing Institute of Nanoenergy and Nanosystems, CAS, and the PLA Strategic Support Force Characteristic Medical Center. Shaobo Wang, Zhao, Zhang and Huang are also affiliated with the Center on Nanoenergy Research, School of Physical Science and Technology, Guangxi University. Yao is also affiliated with the School of Nanoscience and Technology, University of CAS.
The National Natural Science Foundation of China and the National Youth Talent Support Program supported this work.
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