Matthew T. Tung, Tianyi Ma, Ivonne Rebeca Lopez-Miranda, Joshua N. Milstein and Andrew A. Beharry
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引用次数: 0
Abstract
Antimicrobial photodynamic therapy (aPDT) utilizes light, oxygen and a photosensitizer (PS) to enact cell death via the production of reactive oxygen species (ROS). This mechanism of cell death, via oxidative stress, has allowed aPDT to be effective against antibiotic-resistant bacterial strains, with the development of resistance being minimal as no specific pathway is targeted. While promising, as ambient light can activate PSs, damage to mammalian tissues can occur, leading to drug-induced photosensitivity. To mitigate this, we developed a nitroreductase-activatable PS containing a quenching group that inhibits fluorescence and ROS. Upon reaction with nitroreductase, the quenching group can be liberated, restoring fluorescence and ROS production. As nitroreductase is not present in healthy mammalian tissues but expressed in many bacteria, photosensitivity of mammalian cells can be reduced. Herein, the synthesis and photophysical characterization of the nitroreductase-activatable PS, DB2, is described. DB2 was quenched compared to the free PS, DB1, and activation both in vitro by purified nitroreductase and in the gram-positive bacterial strain, Bacillus subtilis, was confirmed by fluorescence recovery. Cell viability studies in B. subtilis showed low dark toxicity and an IC50 of 0.16 μM under 10-minute irradiation (530 nm, 42 mW cm−2). Minimal toxicity was observed under the same conditions in mammalian cell cultures demonstrating the potential of DB2 to mitigate photosensitivity and provide a promising approach for aPDT.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.