A carnitine-based BODIPY photosensitizer

Abstract

Organelle-selective photodynamic therapy (PDT) has emerged as a promising approach to enhance the precision and efficacy of cancer treatment by targeting key cellular structures. In this study, we report the design of a novel carnitine-based BODIPY photosensitizer, probe 1, which retains mitochondrial selectivity while acting as both a fluorescent probe and a potent photosensitizer. Building on our previously developed mitochondria-targeting probe (R)-BCT-2, which is transported into the mitochondrial matrix by the inner membrane protein carnitine–acylcarnitine translocase (CAC), probe 1 incorporates two bromine atoms that enhance intersystem crossing, leading to a singlet oxygen quantum yield of ∼80%, while retaining sufficient fluorescence for effective cell staining in fluorescence microscopy. Theoretical calculations indicate that the carnitine moiety distorts chromophore planarity, reducing oscillator strength but enhancing spin–orbit coupling, which, together with the extended triplet lifetime, contributes to increased phototoxicity. Probe 1 co-localizes in both mitochondria and, to a lesser extent, in lysosomes, and this dual targeting may synergistically enhance phototoxic activity by amplifying cellular stress responses. Importantly, probe 1 demonstrated high phototoxicity upon green light irradiation, with IC₅₀ values of 52 nm under normoxia and 117 nm under hypoxia, while remaining non-cytotoxic in the dark. These results suggest that probe 1 is a promising candidate for organelle-targeted PDT, particularly in hypoxic tumor environments where its dual organelle targeting could enhance therapeutic efficacy.