Intracellular Generation of Alkyl Radicals Enabled by a Self-Catalytic ATRP Nanoinitiator

Oxygen-independent alkyl radicals (R^•) have demonstrated great promise in combating tumor hypoxia. Currently, Azo compounds have been the primary source of R^•, suffering from external stimuli and decomposition during circulation. Herein, we developed a self-catalytic ATRP nanoinitiator that could generate R^• via glutathione (GSH) reduction and thus selectively induce apoptosis of tumor cells. Specifically, a conjugation of laccase (possessing a copper(II) complex) and polymeric alkyl bromide, poly(iBBr), was fabricated to yield an ATRP nanoinitiator (Lac-P(iBBr)). After internalization by cells featured with overexpressed GSH, copper(II) in Lac-P(iBBr) was reduced to copper(I) by GSH, which abstracted the Br atom in poly(iBBr) to yield toxic R^•. Moreover, GSH-depletion intensified the oxidative damage caused by R^•. Efficient generation of R^• by Lac-P(iBBr) could happen in lab flasks, living cells, and tumor-bearing mice without any external stimuli, as demonstrated by the radical product, as well as the consumption of GSH. Moreover, the self-catalytic ATRP nanoinitiator significantly induced cell apoptosis and suppressed tumor growth. Our study expands the chemical toolbox to manipulate cell fates.