LIGHTING UP HYPOXIC TUMORS WITH A NONCANONICAL AMINO ACID

摘要

Cancer researchers have long known that malignant tissue tends to be hypoxic, with increasing levels of hypoxia linked to less success with chemotherapy and radiation. The enzyme nitroreductase (NTR) is often overexpressed in hypoxic regions of solid tumors. Although a considerable number of NTR-responsive systems have been developed, few reliable strategies have been reported for manipulating the self-assembly of peptides through NTR reduction of amino acids, thus limiting the development of NTR-responsive peptide-based biomaterials. Zhilin Yu and co-workers address this challenge by developing the synthetic NTR-responsive amino acid 2-nitroimidazol-1-yl alanine, or A(2NI), through the Mitsunobu reaction between 2-nitroimidazole and a serine derivative, and then incorporating it into peptide sequences through rational design (DOI: 10.1021/jacs.1c06435). In vitro experiments showed that, in the presence of NTR, these assembled peptide nanofibrils transformed into nanoparticles. Although attached fluorescent dye molecules were quenched in individual peptides, exposure of the self-assembled peptides to NTR inhibited the quenching pathway, allowing the resulting nanoparticles to glow. The researchers demonstrated the peptides' utility in mouse models of breast cancer as probes that caused hypoxic tumors to fluoresce. The authors suggest this self-assembly strategy could provide a powerful toolkit for synthetic biology and the development of novel biomaterials.