Heavy atom engineering of Ru(ii) complex based sonosensitizers for enhancing antifungal therapy†

Despite the advances in antifungal therapy in the past decade, the issues of fungal resistance and the lack of effective treatments are still of major concern in clinical practice. Recently, sonodynamic therapy (SDT) has been at the forefront of the research in biomedicine, yet the employment of sonosensitizers and SDT on antifungal infections is still in its early stages. Herein, we designed and synthesized a series of Ru(II) complex-based sonosensitizers (RuH–RuBr) with enhanced ultrasound-triggered ROS generation for antifungal applications. The heavy atom (etc. Br) engineering strategy has been well employed to narrow the HOMO–LUMO energy gap of Ru(II) sonosensitizers, particularly in RuBr, which resulted in a significant boost in ROS generation (11.8 fold). In vitro results indicated that RuBr demonstrated both good anti-Candida albicans activity (MIC = 5 μM) and low mammalian cell toxicity (survival rate > 80%) under US irradiation. Further mechanism investigation suggested that RuBr initially aggregated on the fungal cell membrane and subsequently led to ultrasound-activated ROS accumulation, resulting in mitochondrial damage and triggering changes in the mitochondrial membrane potential. In vivo studies also revealed that RuBr exhibited similar antifungal performance but lower systemic toxicity when compared to the conventional clinical antifungal amphotericin B (AmB). This research offers significant insights into the design of high-performance sonosensitisers and lays the foundation for innovative antifungal therapeutic strategies.