High-Throughput Preparation of Radioprotective Polymers via Hantzsch’s Reaction for In Vivo X-ray Damage Determination
Story behind this article (Nat. Commun. 10.1038/s41467-020-20027-0): how did this project come about and some of the research results.
In the future, mankind will surely step out of the earth cradle and enter the sea of stars. Humans will encounter many difficulties in the future star travels, high energy cosmic ray is one of the main obstacles. People should be well ready to face the inevitable strong ionizing radiation during deep-space travels that may require years or even decades. Meanwhile, modern society is also facing accidental nuclear leakages and potential terrorist attacks that considerably increase the risk of exposure to high doses of ionizing radiation. At present, amifostine is the only approved radioprotector that was explored by the Anti-radiation Drug Development Program of the U.S. Army. However, amifostine is rapidly excreted by the human body and has serious side effects even at low doses. This considerably limits its application to counteract injuries caused by high doses of ionizing radiation. Thus, safe and efficient radioprotectors for acute injuries caused by large doses of ionizing radiation are vital to national security, public health and future development of humankind.
In 2017, during our research to develop a high throughput (HTP) method to modify polymer side groups through multicomponent reactions (MCRs), we found by chance some polymers are excellent antioxidants (Polym. Chem. 2017, 8, 5679-5687). In 2018, we used essential oil extracts to develop some interesting antioxidant polymers through MCRs in an HTP manner. A screened polymer is better than superoxide dismutase (SOD) in protecting cells from fatal UV irradiation (JACS, 2018, 140, 6865-6872). In 2019, we enhanced the antioxidant ability of polymers by including ferrocene moieties into polymer structures through MCRs. The obtained polymer is better than silymarin (an active ingredient in clinically prescribed medicine) in counteracting oxidative stress-induced acute liver injury (ACS Macro Lett., 2019, 8, 639-645). These studies suggest the combination of MCRs and HTP methods is valid to explore macromolecular antioxidants that may solve some problems associated with the use of small molecules (e.g. quick elimination from the body, poor water solubility, instability and toxicity); they also encourage us to develop safe and efficient macromolecular radioprotectors.
In our recent work (Nat. Commun. 10.1038/s41467-020-20027-0), we developed a strategy to explore bio-friendly radioprotectors by combining Hantzsch’s reaction, HTP methods and polymer chemistry. A water-soluble polymer with low-cytotoxicity and excellent anti-radiation capability was achieved. In in vivo experiments, this polymer is better than amifostine in effectively protecting zebrafish embryos from fatally large doses of ionizing radiation (80 Gy X-ray). A mechanistic study revealed that the radioprotective ability of this polymer originated from its ability to efficiently prevent DNA damage due to high doses of radiation.
This is an initial attempt to explore polymer radioprotectors via MCRs. It offers new insights into developing new radioprotectors by the combination of MCRs and polymer chemistry. The current research is promising but still has room for improvement: 1) the polymer that is better than amifostine in protecting zebrafish from high doses of ionizing radiation may not work in mammals; 2) this research reveals few clues for de novo designing bio-friendly polymer radioprotectors; 3) polymers in this research are not biodegradable. In our future research, we will address these deficiencies by the combination of MCRs, HTP methods, modern polymerization technologies, and theoretical calculation to identify new macromolecular radioprotectors for real applications.