Expanding the toolbox of bioorthogonal activation of photosensitizers for precise photodynamic therapy through transition metal-mediated deallylation

The development of bioorthogonal activation of photosensitizers represents a promising avenue for precise photodynamic therapy (PDT) against cancer. It requires effective decaging strategies that can be applied in vivo, but such highly efficient and biocompatible methodologies remain scarce. We report herein the first use of ruthenium-mediated bioorthogonal deallylation for on-demand activation of boron dipyrromethene (BDP)-based photosensitizers. In this study, we first prepared a series of BDP-based photosensitizers connected to an allyl group with or without a self-immolative spacer via an ester caging unit [<b>Pro-BDP-n</b> (n = 1-4)] and studied their activation upon treatment with several ruthenium complexes [<b>RuLn</b> (n = 1-3)]. <b>Pro-BDP-3</b>, having a methoxy substituent at the self-immolative linker, was found to exhibit the highest release efficiency and fastest decaging kinetics. Using <b>RuL3</b> as activator, which was modified with a biotin moiety, <b>Pro-BDP-3</b> could be selectively activated in the endoplasmic reticulum (ER) of biotin receptor-overexpressed cancer cells. The induced ER stress disturbed the intracellular calcium homeostasis and ER-mitochondria crosstalk, resulting in mitochondria dysfunction and eventually cell death via apoptosis. The high treatment efficacy of this approach was also demonstrated in vivo. This work expands the toolbox of bioorthogonal activation of photosensitizers using transition metal-promoted deallylation as an efficient decaging strategy.