Heavy Atom engineering of Ru(II) Complex based Sonosensitizers for Enhancing Antifungal Therapy

Abstract

Despite advance on antifungal therapy in the past decade, the issues of fungal resistance and a lack of effective treatments are still of major concern in clinical practice. Recently, sonodynamic therapy (SDT) is at the forefront of the research on biomedicine, yet, the employment of sonosensitizers and SDT on antifungal infections is still on its early stages. Herein, we designed and synthesized a series of Ru(II) complex-based sonosensitizers (RuH-RuBr) with enhancing 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 cells toxicity (survivial rate > 80%) under US irradiation. Further mechanism investigation suggested RuBr initially aggregated on the fungal cell membrane and subsequently ultrasound-activated ROS accumulation, leading to mitochondrial damage and triggering changes of 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 offered significant insights into the design of high-performance sonosensitisers and lay the foundation for innovative antifungal therapeutic strategies.