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

Abstract

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 <b>BODIPY</b> photosensitizers (<b>R-BOD</b>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 <b>BODIPY</b> along with the introduction of different functional groups at the <i>meso</i>-position of the <b>BODIPY</b> core is essential for tuning the photophysical and photosensitizing properties. Notably, the MeOPh-substituted thiophene-fused <b>BODIPY</b> (<b>MeO-BOD</b>, R = <i>p</i>-methoxyphenyl) displayed the highest singlet oxygen generation capability (<i>Φ</i> _Δ ≈ 0.85 in air-saturated acetonitrile) and a moderate fluorescence quantum yield (<i>Φ</i> _f = 17.11). Furthermore, <b>MeO-BOD</b> showed good biocompatibility, low dark toxicity and superior fluorescence imaging properties in living cells. More importantly, the PDT efficacy of mitochondria-specific anchoring of <b>MeO-BOD</b> was remarkably amplified with an extremely low half-maximal inhibitory concentration (IC₅₀) value of 95 nM. We believe that the incorporation of an electron-donating group at the <i>meso</i>-position of the thiophene-fused <b>BODIPY</b> platform may be an effective approach for developing theranostic agents for precision cancer therapy.