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.