Bridging D–A type photosensitizers with the azo group to boost intersystem crossing for efficient photodynamic therapy

Abstract

Photodynamic therapy (PDT) has attracted much attention in disease treatments. However, the exploration of a novel method for the construction of outstanding photosensitizers (PSs) with stimuli-responsiveness remains challenging. In this study, we, for the first time, report a novel and effective strategy to boost reactive oxygen species (ROS) generation by bridging donor–acceptor (D–A) type PSs with the azo group. In contrast to the counterpart without azo-bridging, the azo-bridged PSs exhibit remarkably enhanced ROS generation via both type-I and type-II photochemical reactions. Theoretical calculations suggest that azo-bridging leads to a prominent reduction in ΔE_ST, thereby enabling enhanced ROS generation via efficient intersystem crossing (ISC). The resulting azo-bridged PS (denoted as Azo-TPA-Th(+)) exhibits a particularly strong bactericidal effect against clinically relevant drug-resistant bacteria, with the killing efficiency up to 99.999999% upon white light irradiation. Since azo-bridging generates an azobenzene structure, Azo-TPA-Th(+) can undergo trans-to-cis isomerization upon UV irradiation to form emissive aggregates by shutting down the ISC channel. By virtue of the fluorescence turn-on property of unbound Azo-TPA-Th(+), we propose a straightforward method to directly discern the effective photodynamic bactericidal dose without performing the tedious plate-counting assay. This study opens a brand-new avenue for the design of advanced PSs with both strong ROS generation and stimuli-responsiveness, holding great potential in high-quality PDT with rapid prediction of the therapeutic outcome.