Acid-Responsive Thiocarbonylated Coumarin Photosensitizer for Hypoxia-Tolerant Photodynamic Therapy
Gahyun Kim, Van Kieu Thuy Nguyen, JeongHye Han, Lei Cao, Sang Gil Lee, Sang Gil Lee, Dai Lam Tran, Thanh Chung Pham, Songyi Lee, Songyi Lee
Abstract
The potential off-target toxicity of conventional organic photosensitizers (PSs) and their lack of specificity for tumor tissues necessitate the development of alternatives selectively activatable within the tumor microenvironment, which is typically characterized by increased acidity. To address this need, we prepared a morpholine-group-bearing thiocarbonylated Coumarin 343 (CS) as an acid-targeted PS. CS exhibits a negligible fluorescence emission and singlet oxygen generation under neutral conditions while being activated under acidic conditions. The emission of protonated CS is enhanced due to promotion of the oscillator strength of the 1 π–π* transition. Its spin–orbit coupling between the first singlet and triplet excited states is enhanced because of a shift in the nature of the first singlet excited state from charge transfer to 1 n–π* and driven by El-Sayed’s rule. In addition, experimental and computational results indicate that CS can generate reactive oxygen species via a Type I mechanism. In vitro study, CS exhibits strong fluorescence imaging in HeLa cells and high photocytotoxicity under both normoxic and hypoxic conditions. Thus, this study provides a rational molecular design strategy for smart PSs and paves the way for the precise photodynamic therapy of hypoxic tumors.