Increasing Photothermal Efficacy By Simultaneous Intra- And Intermolecular Fluorescence Quenching

Recently, using in situ self-assembly-induced fluorescence quenching (i.e., intermolecular quenching denoted herein) of a photothermal agent (PTA) to enhance its photothermal efficiency has proven to be a successful photothermal therapy (PTT) strategy. But to the best of current knowledge, using simultaneous intra- and intermolecular fluorescence quenching of a PTA to additionally increase its photothermal efficacy has not been reported. Herein, employing a click condensation reaction and a rationally designed PTA Biotin-Cystamine-Cys-Lys(Cypate)-CBT (1), a "smart" strategy is developed of intracellular simultaneous intra- and intermolecular fluorescence quenching and applied it to largely increase the photothermal efficacy of the agent both in vitro and in vivo. After being internalized by biotin receptor-overexpressing cancer cells, 1 is reduced by intracellular glutathione to initiate a CBT-Cys condensation reaction (intramolecular quenching) and self-assembly (intermolecular quenching) to form the nanoparticles 1-NPs (simultaneous intra- and intermolecular fluorescence quenching). Experimental results indicate that 1-NPs have higher fluorescence quenching efficiency than the control PTAs [Thiazole-Lys(Cypate)-Benzothiazole](2) (1-Dimer, intramolecular quenching), and nanoparticles of Cystamine-Cys(Fmoc)-Lys(Cypate)-CBT (1-Fmoc-NPs, intermolecular quenching). It is envisioned that, by replacing the biotin group on 1 with other targeting warheads, the "smart" strategy is ready to increase the photothermal therapeutic efficiency of their corresponding diseases.