Photochemical internalisation: the journey from basic scientific concept to the threshold of clinical application

Efficient delivery of therapeutic agents to subcellular targets is a major challenge in pharmacology. Physical properties including size and charge may adversely affect the cellular uptake of molecules, and consequently reduce the accessibility of intracellular targets. For example macromolecules, which do not pass freely through the phospholipid membrane, are internalised via endocytosis and subsequently retained in endosomes or lysosomes before enzymatic degradation or cell efflux. Photochemical internalisation (PCI) is a novel drug delivery technology based on light-activated release of biologically active compounds retained within endosomes/lysosomes. PCI is founded upon the principle of photodynamic therapy (PDT), which uses light to activate photosensitisers to ultimately produce reactive oxygen species (ROS) and cause local damage/cell death. In PCI, photosensitisers are selectively localised in endosomal/lysosomal membranes. PCI triggers membrane rupture facilitating release and delivery of endocytosed molecules to intracellular targets.

► PCI is a light and oxygen dependent cellular delivery technique for macromolecules. ► In vitro PCI has been shown to reverse multidrug resistance in cancer cells. ► In vivo PCI has been shown to be effective in inhibiting tumour regrowth. ► PCI is currently being evaluated for clinical application in head and neck cancer.