Could clinical photochemical internalisation be optimised to avoid neuronal toxicity?

Caitriona O’Rourke,Colin Hopper,Alexander J Macrobert,James B Phillips,Josephine H Woodhams

doi:10.1016/j.ijpharm.2017.05.071

Abstract

Photochemical Internalisation (PCI) is a novel drug delivery technology in which low dose photodynamic therapy (PDT) can selectively rupture endo/lysosomes by light activation of membrane-incorporated photosensitisers, facilitating intracellular drug release in the treatment of cancer. For PCI to be developed further, it is important to understand whether nerve damage is an impending side effect when treating cancers within or adjacent to nervous system tissue. Dorsal root ganglion (DRG) neurons and their associated satellite glia were subjected to PCI treatment in a 3D co-culture system following incubation with photosensitisers: meso-tetraphenylporphine (TPPS2a) or tetraphenylchlorin disulfonate (TPCS2a) and Bleomycin. Results from the use of 3D co-culture models demonstrate that a cancer cell line PCI30 and satellite glia were more sensitive to PCI than neurons and mixed glial cells, athough neurite length was affected. Neurons in culture survived PCI treatment under conditions sufficient to kill tumour cells, suggesting cancers within or adjacent to nervous system tissue could be treated with this novel technology.

Highlights

Photochemical Internalisation (PCI) is a novel photochemical technology that facilitates the delivery of molecules into the cytosol of the cell
The membrane rupture occurs through oxidative damage from Reactive oxygen species (ROS) generated by the photosensitiser, but the light and photosensitiser doses used in PCI are too small to exert a lethal effect (in contrast to Photodynamic therapy (PDT), where the reactive oxygen species (ROS) damage induced by the photosensitiser is directly cytotoxic)
For Tetraphenylchlorin disulfonate (TPCS2a), both Pearson’s correlation coefficient and overlap coefficient values were higher in PCI30 cells at all concentrations compared to mixed glial cells and Dorsal root ganglion (DRG)/satellite glia, suggesting a greater proportion of photosensitiser could be located within the endosomes of the cancer cell line

Summary

Introduction

Photochemical Internalisation (PCI) is a novel photochemical technology that facilitates the delivery of molecules into the cytosol of the cell. In PCI, a photosensitiser together with a therapeutic agent taken up via endocytosis. Exposure to light leads to endosomal rupture and the release of the therapeutic agent into the cytosol. The membrane rupture occurs through oxidative damage from ROS generated by the photosensitiser, but the light and photosensitiser doses used in PCI are too small to exert a lethal effect (in contrast to Photodynamic therapy (PDT), where the reactive oxygen species (ROS) damage induced by the photosensitiser is directly cytotoxic). By harnessing the improved delivery efficiency conferred by PCI, many of the unwanted side effects associated with using drugs with a molecular weight in excess of 1000 Da are reduced. For example it has been estimated that, once in the cytosol, as few as $500 Bleomycin molecules are sufficient to kill a cell (Poddevin et al, 1991)

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