H ‐Aggregated Cationic Isomers to Boost ROS Generation for Photodynamic Therapy

ABSTRACT Photodynamic therapy (PDT) has become a burgeoning alternative modality in clinics to treat cancer, and photosensitizers are the critical components for PDT. Herein, considering that the radiative transition from the S 1 to S 0 energy states in H ‐aggregates is symmetry‐forbidden, we proposed that H ‐aggregates were more prone to undergo intersystem crossing (ISC), thereby generating a photodynamic effect. Based on this hypothesis, we have successfully designed and synthesized a pair of isomers with planar structure, 2‐IVQ and 4‐IVQ, to seek for an efficient sensitizer working on H ‐aggregation mechanism. 2‐IVQ tends to form H ‐aggregates more readily, and the formation of H ‐aggregates at high concentrations actually enables effective generation of the photodynamic effect. Interestingly, at low concentrations, 2‐IVQ exhibits a weaker photodynamic effect compared to 4‐IVQ, which further supports the formation of H ‐aggregates in 2‐IVQ at high concentrations. Concentrated in mitochondria of cancer cells, tightly H ‐aggregated 2‐IVQ showed faster ROS generation that induced cell apoptosis, and could self‐report entire PDT process by visualizing the dyeing position change from mitochondria to nucleolus. In addition, 2‐IVQ had a substantial antitumor effect in H460 tumor bearing mice. This work provides a new strategy to promote the ISC for constructing effective phototheranostic reagents based on H ‐aggregation mechanism.