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

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 S₁ to S₀ 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.