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000303087 1001_ $$aPeng, Wenwu$$b0
000303087 245__ $$aAutonomous Activation of a Gated Chemiluminescent Photosensitizer Enables Targeted Photodynamic Therapy in Tumor Cells.
000303087 260__ $$aWashington, DC$$bACS Publications$$c2025
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000303087 520__ $$aChemiluminescence-based photodynamic therapy (CLPDT) offers a promising solution to the light penetration limits of traditional PDT. However, it lacks spatiotemporal control. Intracellularly activated, self-luminescent PDT agents via a molecular logic gate switch may address this key limitation. We report the synthesis of the self-activating, chemiluminescent photosensitizer (PS) that enables tumor microenvironment-controlled PDT applications. This system integrates a dioxetane-based (Diox) chemiluminescent scaffold with a ruthenium-based (Ru) PS through an oxidation and pH-sensitive linker to enable an AND-gated activation mechanism. The Diox@Ru conjugate is selectively activated by elevated intracellular reactive oxygen species (ROS), characteristic of aggressive cancer phenotypes arising from altered cell metabolism. Upon exposure to ROS (in this case, hydrogen peroxide), the boronic acid ester protecting group of the dioxetane is cleaved, initiating localized chemiluminescence that directly excites the Ru(II) PS to generate cytotoxic singlet oxygen (1O2). Importantly, Diox@Ru remains inert under physiological conditions (neutral pH, low ROS) as well as in the acidic, ROS-rich extracellular tumor milieu (slightly acidic, high ROS). Its activation is confined to the intracellular space of glycolytic cancer cells with mildly alkaline, ROS-rich cytoplasm; and proceeds autonomously, without the need for external light irradiation. In both two-dimensional (2D) monolayer cultures and three-dimensional (3D) tumor spheroid models, Diox@Ru exhibits robust luminescence and efficient 1O2 production, resulting in potent cytotoxic effects. These findings present a versatile platform for autonomous activation of self-luminescent PDT agents and highlight the promise of logic-gated chemiluminescence for spatially controlled therapy in complex biological settings.
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000303087 7001_ $$aZhou, Tianjiao$$b1
000303087 7001_ $$aHu, Lifan$$b2
000303087 7001_ $$aVankann, Vivien$$b3
000303087 7001_ $$0P:(DE-HGF)0$$aBohn, Toszka$$b4
000303087 7001_ $$0P:(DE-HGF)0$$aBopp, Tobias$$b5
000303087 7001_ $$00000-0003-3945-4491$$aKuan, Seah Ling$$b6
000303087 7001_ $$00000-0002-5906-7205$$aWeil, Tanja$$b7
000303087 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/jacs.5c06761$$gp. jacs.5c06761$$n31$$p27822-27834$$tJournal of the American Chemical Society$$v147$$x0002-7863$$y2025
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