A GSH‐Responsive Prodrug with Simultaneous Triple‐Activation Capacity for Photodynamic/Sonodynamic Combination Therapy with Inhibited Skin Phototoxicity

Abstract Herein, a dual‐sensitizer prodrug, named pro‐THPC, has been designed to function as both a photosensitizer and a sonosensitizer prodrug for precise antitumor combination therapy with minimized skin phototoxicity. Pro‐THPC could be activated by glutathione (GSH) to release the dual‐sensitizer, THPC, which simultaneously switches on fluorescence emission and combined capabilities of photodynamic therapy (PDT) and sonodynamic therapy (SDT). Pro‐THPC is further formulated into nanoparticles (NPs) for water dispersity to enable in vivo applications. In vivo fluorescence imaging shows that the pro‐THPC NPs group exhibits a significantly higher tumor‐to‐normal tissue ratio ( T / N ) ( T / N = 5.2 ± 0.55) compared to the “always on” THPC NPs group ( T / N = 2.9 ± 0.47) and the pro‐THPC NPs group co‐administrated with GSH synthesis inhibitor (buthionine sulfoximine, BSO) ( T / N = 3.2 ± 0.63). In addition, the generation of the designed dual‐sensitizer's reactive oxygen species (ROS) is effectively confined within the tumor tissues due to the relatively strong correlation between ROS generation and fluorescence emission. In vivo studies further demonstrate the remarkable efficacy of the designed pro‐THPC NPs to eradicate tumors through the combination of PDT and SDT while significantly reducing skin phototoxicity.