Fine-tuning the electronic structure of heavy-atom-free photosensitizers for fluorescence imaging and mitochondria-targeted photodynamic therapy.

Theranostics that combines both diagnosis and therapy into a single platform has recently emerged as a promising biomedical approach for cancer treatment; however, the development of efficient theranostic agents with excellent optical properties remains a challenge. Here, we report novel mitochondria-targeting photosensitizers (s) that possess considerable singlet oxygen generation capabilities and good fluorescence properties for imaging-guided photodynamic therapy (PDT). The incorporation of sulfur atoms into the π-conjugated skeleton of along with the introduction of different functional groups at the -position of the core is essential for tuning the photophysical and photosensitizing properties. Notably, the MeOPh-substituted thiophene-fused (, R = -methoxyphenyl) displayed the highest singlet oxygen generation capability ( ≈ 0.85 in air-saturated acetonitrile) and a moderate fluorescence quantum yield ( = 17.11). Furthermore, showed good biocompatibility, low dark toxicity and superior fluorescence imaging properties in living cells. More importantly, the PDT efficacy of mitochondria-specific anchoring of was remarkably amplified with an extremely low half-maximal inhibitory concentration (IC) value of 95 nM. We believe that the incorporation of an electron-donating group at the -position of the thiophene-fused platform may be an effective approach for developing theranostic agents for precision cancer therapy.