Radioprotectors for acute injuries caused by large doses of ionizing radiation are vital to national security, public health and future development of humankind. Here, we develop a strategy to explore safe and efficient radioprotectors by combining Hantzsch’s reaction, high-throughput methods and polymer chemistry. A water-soluble polymer with low-cytotoxicity and an excellent anti-radiation capability has been achieved. In in vivo experiments, this polymer is even better than amifostine, which is the only approved radioprotector for clinical applications, in effectively protecting zebrafish embryos from fatally large doses of ionizing radiation (80 Gy X-ray). A mechanistic study also reveals that the radioprotective ability of this polymer originates from its ability to efficiently prevent DNA damage due to high doses of radiation. This is an initial attempt to explore polymer radioprotectors via a multi-component reaction. It allows exploiting functional polymers and provides the underlying insights to guide the design of radioprotective polymers.

Small-molecule antioxidants perform poorly in vivo in combating oxidative stress because of their low bioavailability. Water-soluble polymeric antioxidants can overcome the limitations of small molecular antioxidants (instability, poor water solubility, fast metabolism, etc.), but there are only a few efficient synthesis methods to prepare safe and effective polymeric antioxidants. In this study, we develop a series of antioxidant polymers containing ferrocene and/or indole moieties through the Ugi four-component reaction and simple free radical polymerization. These polymers are screened using different criteria to find a biocompatible antioxidative polymer that effectively inhibits the lethal and teratogenic effects of UV-induced oxidative damage on zebrafish embryos. This study identifies a strategy to use antioxidative polymers in vivo, demonstrates the value of multicomponent reactions in interdisciplinary areas, and provides the underlying insights to guide the design of antioxidant polymeric biomaterials.