The exploration of the mitochondrial apoptotic pathway in living cells is of great significance for achieving tumor diagnosis and treatment. However, visualization of the mitochondrial apoptotic pathway induced by specific proteins has rarely been reported. In this paper, we designed and synthesized a fluorescent probe Cy-JQ1 based on the bromodomain-containing protein 4 (BRD4) inhibition. Cy-JQ1 can affect mitochondrial electron chain transfer and reduce the mitochondrial membrane potential, effectively activating the Bcl-2/Bax/caspase-3 signaling pathway at a concentration of 500 nM and then triggering cell apoptosis. Due to its high specificity and excellent fluorescence properties, the switching of Cy-JQ1 from mitochondria to endoplasmic reticulum could be observed. The difference in fluorescence intensity along the perinuclear aggregates could be well defined as ΔXOR and used as a sensitive indicator of apoptosis. Upon conjugating with polyethylene glycol (PEG) containing disulfide bonds, the performance of the formed nanoprobe (Cy-JQ1-S-S-M) is further enhanced by improving pharmacokinetics and tumor-specific accumulation. This study provides a new analytical method for the dynamic visualization of mitochondria-induced apoptosis pathways triggered by specific proteins, as well as for the development of apoptosis-related target drugs.
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Target-switchable nanoprobe based on BRD4 inhibition for induction and dynamic visualization of the mitochondrial apoptotic pathway.
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