Pancreatic cancer is among the deadliest malignancies, with 1-year survival below 20%. Because diagnosis is often late, many patients cannot undergo surgery and rely on palliative chemotherapy. Regimens such as FOLFIRINOX can extend survival to around 11 months, but toxicity limits their use, creating a need for combinations that are more effective and better tolerated.
Photodynamic therapy (PDT) uses photosensitisers that accumulate in tumours and, upon local light activation, generate reactive oxygen species (ROS) that kill tumour cells while sparing surrounding tissues. Fibres for light delivery can be placed endoscopically, making PDT clinically feasible for pancreatic lesions.
Preclinical investigations demonstrated that combining PDT with oxaliplatin was beneficial, but the underlying mechanisms were unclear. Owing to its hydrophilic nature, oxaliplatin is likely internalised via endocytosis and sequestered within lysosomes – the cell’s garbage disposal system – restricting its bioavailability. It was therefore hypothesised that PDT could permeabilise lysosomal membranes and release endocytosed oxaliplatin into the cytosol (the aqueous component of the cytoplasm), increasing its effectiveness.
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Image: Subsequent administration of oxaliplatin leads to similar endosomal uptake, but the endosomes then fuse with the permeable lysosomes. This results in increased intracellular platinum levels (although sequestration by ATP7B copper chelating proteins or efflux via multidrug resistance protein 1 (MDR1) may occur).