Alloxazine derivatives as multifunctional agents for photodynamic therapy, cancer cell imaging, and cell proliferation inhibition.

Abstract

The development of biocompatible organic photosensitizers remains an important challenge for advancing image-guided photodynamic therapy. Specifically, photosensitizers that combine strong photodynamic activity, fluorescence emission for bioimaging, decrease or stop the proliferation of cancer cells, and allow synthetic accessibility are in high demand. Herein, we report the synthesis and characterization of a new class of alloxazine-based photosensitizers (ANOMe, A8OMe and A7OMe). They are engineered through sugar conjugation and structurally modified at the C7 and C8 positions with electron-donating methoxy groups to tune their photochemistry and photobiology. These photosensitizers exhibit efficient population of long-lived triplet states, near unity singlet oxygen quantum yields, and fluorescence, as revealed by steady-state spectroscopy, time-correlated single-photon counting, and nanosecond transient absorption spectroscopy. Computational studies (DFT and TD-DFT) are combined with experimental data to disclose their electronic relaxation mechanisms. In vitro cellular assays demonstrate that these photosensitizers enter the cytoplasm, generate cytotoxic reactive oxygen species upon light activation, exhibit substantial fluorescence, and can significantly slow down the proliferation of cancer cells in the absence of light. Collectively, the experimental and computational results demonstrate the utility of rationally designed alloxazine derivatives as multifunctional agents for image-guided photodynamic therapy.