Near-infrared triggered anion transport induces cancer cell death

Artificial transmembrane anion carriers (anionophores) have shown potential in biological research and medicine, such as chemother-apeutics to treat channelopathies or as anticancer agents. Stimuli-responsive systems that are controlled by, for example, light, pH, redox, enzymes or membrane potential offer the potential for targeted activation that is essential for therapeutic applications. Photo-activation of ion transport is particularly advantageous because of the possibility of achieving spatio-temporal control, remote ad-dressability, and reduced cytotoxicity. However, poor tissue penetration and undesired cytotoxicity are significant drawbacks to the photo-activated ionophores reported to date which are mostly triggered by UV or violet light. Here, we report BODIPY-based photo-responsive ion transport systems that are activated with 730 nm NIR light that falls in the biological window. The caged anionophores utilize dynamic hydrogen bonding interactions of a 4-hydroxyisophthalamide motif. Caging of the hydroxyl group of the active aniono-phore with BODIPY-photocages that are responsive to NIR light locks the amide proton through six-membered intramolecular hydro-gen bonding, rendering it unavailable for anion recognition and transport. Decaging with NIR irradiation reverses the hydrogen bond-ing pattern to switch on binding, with efficient off-on activation profiles observed in anion transport experiments in large unilamellar vesicles. Analogous experiments in cancer cells with NIR light revealed turn-on transmembrane chloride transport and a dramatic, dose-dependent decrease in cell viability following NIR decaging of the anionophore, demonstrating the potential for NIR-triggered ionophores as a new class of photodynamic therapy for cancer.