Photoredox catalysis may be a general mechanism in photodynamic therapy

Area of Science:

• Photochemistry
• Cancer Therapy
• Molecular Biology

Background:

• Photodynamic therapy (PDT) efficacy can be improved by understanding its photochemical mechanisms of action (MoA).
• Conventional PDT MoAs involve type I (electron transfer) and type II (energy transfer) photoactivation.
• A novel MoA, "photoredox catalysis in cells," proposes disruption of cellular electron transport pathways.

Purpose of the Study:

• To provide evidence for "photoredox catalysis in cells" as a general MoA for PDT.
• To investigate the catalytic conversion of nicotinamide adenine dinucleotide (NAD) to NAD+ by common photosensitizers.
• To design and evaluate a novel molecular targeting photocatalyst (CatER) for PDT applications.

Main Methods:

• Investigated the catalytic conversion of NAD to NAD+ using various photosensitizers (Rose Bengal, BODIPY, etc.).
• Designed and synthesized a molecular targeting photocatalyst, CatER.
• Evaluated CatER's efficacy in inducing pyroptosis, cancer cell targeting, tumor imaging, and tumor growth inhibition in vitro and in vivo.

Main Results:

• Established photosensitizers catalyze the conversion of NAD to NAD+, supporting the "photoredox catalysis in cells" MoA.
• CatER induced pyroptosis via the caspase 3/GSDME pathway.
• CatER demonstrated specific targeting of epidermal growth factor receptor-positive cancer cells, achieved high signal-to-background ratio tumor imaging (SBRTI = 12.2), and showed significant tumor growth inhibition (TGI = 77.1%).

Conclusions:

• "Photoredox catalysis in cells" represents a distinct MoA for PDT, contrasting with traditional type I and type II mechanisms.
• CatER is an effective near-infrared photo-inducer of pyroptotic cell death with promising anti-cancer properties.
• The findings provide a foundation for developing improved phototherapeutic agents incorporating photocatalytic chemistry.