Engineering long-lived charge separation states boosts type-I ROS generation for efficient cancer therapy

Abstract

Organic photosensitizers (PSs) with long-lived charge-separated states (CSs) are optimal for converting photonic energy into reactive oxygen species (ROS) by maximizing the interaction between excited electrons and holes in subsequent photoreactions. However, the substantial consumption of oxygen by the singlet oxygen species produced by these PSs can significantly impede their anticancer efficacy, because of the hypoxia nature of solid tumors. Herein, we present a rational strategy for the structural modification of the well-known Fukuzumi acridinium salt (9-mesityl-10-methylacridinium ion) with long-lived CSs, by incorporating a methyl-substituted diphenylamine group (named MTPAA). This modification significantly enhances type-I ROS generation. The “methyl effect” in MTPAA has distinguished merits of stabilized radical species through resonance, leading to an over 8-fold increase in type-I ROS generation compared to TPAA, which lacks the methyl group. Moreover, cellular experiments show that MTPAA with the “methyl effect” significantly enhances photodynamic therapy efficacy under hypoxic conditions. Our molecular design strategy offers a promising approach to creating high-performance type-I PSs and is anticipated to inspire broader exploration in other photosensitizer systems with long-lived CSs, serving as a versatile strategy for advancing type-I PS development. © 202