Versatile Stimuli-Responsive Controlled Release of Pinanediol-Caged Boronic Esters for Spatiotemporal and Nitroreductase-Selective Glucose Bioimaging

Abstract

Boronic acids have been widely applied in various biological fields, particularly achieving significant practical progress in boronic acid–based glucose sensing. However, boronic acids exhibit nonspecific binding to other nucleophiles, and the inherent lability of boronic esters in biological systems limits their further applications. Herein, we developed a stimuli-responsive controllable caging strategy to achieve photoresponsive spatiotemporally and nitroreductase-responsive cancer cell-selective glucose sensing. We introduced o-/p-nitroaryl-containing self-immolative linkers onto δ-pinanediol derivatives, effectively caging boronic acids and blocking glucose recognition. Upon triggering by specific stimuli, the caged boronic esters decompose, releasing boronic acids and thereby restoring glucose recognition of the diboronic acid–based sensor. The proof of concept was confirmed through intracellular glucose bioimaging in living cells. Upon regional UV irradiation, we could monitor intracellular glucose with excellent spatiotemporal selectivity. Furthermore, we used the cancer biomarker nitroreductases as the internal stimuli and utilized the caged glucose sensor to selectively label hypoxic cancer cells in a cocultured living cell sample. We believe that our stimuli-responsive caging strategies will hold promising potential for the controlled release of other boronic acids in various biological contexts.