Optimizing mitochondrial-targeting groups of positively-charged BODIPY nanoparticles for enhanced photodynamic therapy†

Mitochondria play an important role in regulating programmed cell death and various available mitochondrial-targeting photosensitizers are modified by cationic groups, especially triphenylphosphine (TPP). However, it's still a big challenge to develop novel mitochondrial-targeting photosensitizers, especially those that possess better performance than traditional TPP-modified photosensitizers. In this work, three cationic boron-dipyrromethene (BODIPY) nanoparticles with different mitochondrial-targeting groups (triphenylphosphine, trimethylamine and 1-methylimidazole) were designed and synthesized for enhanced photodynamic therapy. These BODIPY nanoparticles (BDPI NPs) could be endocytosed by various cancer cells and dissociated in the lysosomes. Subsequently, they escaped from the lysosomes due to the “proton-sponge” effect and were enriched on the inner membrane of mitochondria for enhanced photodynamic therapy. BDPI NPs could generate not only singlet oxygen (¹O₂) but also superoxide anions (O₂⁻˙), showing great type I and II photodynamic activity. Compared with TPP and the trimethylamine substitution, the 1-methylimidazole-modified nanoparticles (BDPI-IMA NPs) exhibited the most efficient mitochondrial-targeting capability and the most excellent photodynamic activity. This work highlights the great potential of 1-methylimidazole-modified photosensitizers and nanoparticles as highly efficient mitochondrial-specific probes and phototherapy agents.