Photoredox catalysis may be a general mechanism in photodynamic therapy

Abstract

Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that “photoredox catalysis in cells,” wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD + . This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.

Cutting Off H+ Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells

“…Importantly, in living breast CSC-like SKBR3 cells, such a rapid release was also seen, and the reaction occurred in the mitochondria, as evidenced by colocalized fluorescence imaging between released resorufin and MitoTracker DiOC6 (Figure S15). In the presence of NAC ( N -acetyl- l -cysteine, a ROS scavenger), however, the fluorescence “On” signal in the mitochondria was markedly inhibited (Figure S15). These findings are consistent with the design expectation that Bo-Mt-Ge can localize to the mitochondria and be conditionally activated by peroxide in living cells.…”

From Low to No O2-Dependent Hypoxia Photodynamic Therapy (hPDT): A New Perspective

“…(2) Will photoredox biological catalysis be nextgeneration phototherapy? Artificial photoredox catalysis-based cancer therapy is a rather new addition to the ever-expanding PDT community (as the results show in our JACS 4 and PNAS papers 5 ). This hence provides a large scope for further contributions in terms of both developing biologically benign photocatalysts and exploring new photoredox reactions in living systems.…”

“…Motivated by these findings, we were curious about how general this MoA (i.e., photoredox catalysis) would be in PDT and surprisingly found that common PSs, such as transition metal complex, BODIPY, Rose Bengal, porphyrin, and phthalocyanine, are all capable of triggering a photoredox NADH catalysis, which means that "photoredox catalysis in cells" might be a general mechanism behind PDT (Figure 11). 5 We believe that exploring the power of artificial photoredox chemistry in the biomedical area would open unforeseen opportunities for metabolic or genetic interventions and unveil new photochemical techniques for clinical disease diagnosis and therapy.…”

“…Photodynamic therapy (PDT), a photon-triggered therapeutic strategy that involves the synergistic utilization of light, photosensitizer (PS), and molecular oxygen (O 2 ) to produce cytotoxic reactive oxygen species (ROS) and eradicate localized tumor cells, has garnered ever-increasing attention in clinical cancer therapy. − It has unique merits such as minimal invasiveness, remote control, and fast and cost-efficient operation. In some situations, PDT has even been demonstrated to be effective where treatments like surgery, chemical therapy, and radiation therapy have failed.…”

Boosting Type-I and Type-II ROS Production of Water-Soluble Porphyrin for Efficient Hypoxic Tumor Therapy

“…Photodynamic therapy (PDT) has attracted great attention in curing cancers due to its minimal invasiveness and side effects, spatiotemporal selectivity, and high therapeutic efficacy compared to conventional cancer treatments. − In PDT, the photoexcited photosensitizers (PSs) convert triplet oxygen and other molecules into cytotoxic reactive oxygen species (ROS) via electron transfer (type-I) or energy transfer (type-II), which subsequently induce apoptosis or necrosis of tumor cells. − However, the high hydrophobicity-caused aggregation of PSs under physiological conditions usually results in significant self-quenching of excitons, thereby decreasing their ROS generation efficacy severely. ,, Additionally, the hypoxic microenvironment of solid tumors further hinders most type-II PSs from achieving satisfactory in vivo PDT performance. ,,− …”