TY  - JOUR
AU  - Peng, Wenwu
AU  - Zhou, Tianjiao
AU  - Hu, Lifan
AU  - Vankann, Vivien
AU  - Bohn, Toszka
AU  - Bopp, Tobias
AU  - Kuan, Seah Ling
AU  - Weil, Tanja
TI  - Autonomous Activation of a Gated Chemiluminescent Photosensitizer Enables Targeted Photodynamic Therapy in Tumor Cells.
JO  - Journal of the American Chemical Society
VL  - 147
IS  - 31
SN  - 0002-7863
CY  - Washington, DC
PB  - ACS Publications
M1  - DKFZ-2025-01512
SP  - 27822-27834
PY  - 2025
N1  - 2025 Aug 6;147(31):27822-27834
AB  - Chemiluminescence-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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40696775
DO  - DOI:10.1021/jacs.5c06761
UR  - https://inrepo02.dkfz.de/record/303087
ER  -