Potent BODIPY-based photosensitisers for selective mitochondrial dysfunction and effective photodynamic therapy

The development of new and improved mitochondria-targeting photosensitisers (PSs) for photodynamic therapy (PDT) remains highly desirable, due to the critical role the mitochondria play in maintaining healthy cellular function. Here, we report the design, synthesis, photophysical properties and biological characterisation of a series of di-iodinated BODIPY-based PSs, BODIPY-Mito-I-n, for mitochondria-targeted PDT applications. Six BODIPY-Mito-I-n analogues were synthesised in good yields, with fast reaction times of between 30 and 60 min under mild conditions. The di-iodination of the BODIPY scaffold enabled highly efficient population of the triplet state, leading to high singlet oxygen (¹O₂) photosensitisation efficiencies (Φ_Δ = 0.55–0.65). All BODIPY-Mito-I-n compounds exhibited very high photocytotoxic activity towards HeLa cells, with IC_50,light values of between 1.30 and 6.93 nM, due to photoinduced ¹O₂ generation. Notably, the poly(ethylene glycol) (PEG)-modified BODIPY-Mito-I-6 showed remarkably lower dark cytotoxicity (IC_50,dark = 6.68–7.25 μM) than the non-PEGylated analogues BODIPY-Mito-I-1 to BODIPY-Mito-I-5 (IC_50,dark = 0.58–1.09 μM), resulting in photocytotoxicity indices up to 2120. Mechanistic studies revealed that BODIPY-Mito-I-6 induced reactive oxygen species overproduction and mitochondrial dysfunction in cells upon irradiation, leading to significant cell death through a combination of apoptosis and necrosis. It is anticipated that our design will contribute to the development of more effective mitochondria-targeting PSs for cancer therapy.