A novel zinc phthalocyanine-indometacin photosensitizer with “Three-in-one” cyclooxygenase-2-driven dual targeting and aggregation inhibition for high-efficient anticancer therapy

Photodynamic therapy, during which nontoxic photosensitizers can be photo-activated to generate cytotoxic reactive oxygen species, has attracted great interest. However, the strong aggregation and poor tumor targeting of photosensitizers, the short action radius and lifetime of reactive oxygen species limit the therapeutic efficiency greatly. Herein, indomethacin, an inhibitor and substrate of cyclooxygenase-2, is introduced to conjugate with zinc phthalocyanines for successively solving these three problems. Own to indomethacin moiety, our designed photosensitizer IMC-Pc can bind to cyclooxygenase-2 with reduced aggregation, and its binding mechanism was demonstrated by fluorescence enhancement and docking calculations. Subsequently, the indomethacin moiety assists ZnPc selectively targeting to cyclooxygenase-2 expressive tumor cells, and further accumulating in Golgi apparatus. Importantly, our results exhibit the improved intracellular reactive oxygen species generation and enhanced anticancer efficacy of IMC-Pc. Overall, such a novel photosensitizer with “three-in-one” cyclooxygenase-2-driven dual targeting and aggregation inhibition is a promising candidate for improving therapeutic efficacy.