Efficacy of photochemical internalisation using disulfonated chlorin and porphyrin photosensitisers: An in vitro study in 2D and 3D prostate cancer models

Abstract

This study shows the therapeutic outcome of Photochemical Internalisation (PCI) in prostate cancer in vitro surpasses that of Photodynamic Therapy (PDT) and could improve prostate PDT in the clinic, whilst avoiding chemotherapeutics side effects. In addition, the study assesses the potential of PCI with two different photosensitisers (TPCS2a and TPPS2a) in prostate cancer cells (human PC3 and rat MatLyLu) using standard 2D monolayer culture and 3D biomimetic model. Photosensitisers were used alone for photodynamic therapy (PDT) or with the cytotoxin saporin (PCI). TPPS2a and TPCS2a were shown to be located in discrete cytoplasmic vesicles before light treatment and redistribute into the cytosol upon light excitation. PC3 cells exhibit a higher uptake than MatLyLu cells for both photosensitisers. In the 2D model, PCI resulted in greater cell death than PDT alone in both cell lines. In 3D model, morphological changes were also observed. Saporin-based toxicity was negligible in PC3 cells, but pronounced in MatLyLu cells (IC50 = 18 nM). In conclusion, the study showed that tumour features such as tumour cell growth rate or interaction with drugs determine therapeutic conditions for optimal photochemical treatment in metastatic prostate cancer.

Could clinical photochemical internalisation be optimised to avoid neuronal toxicity?

“…Comparing the photosensitiser fluorescence levels in each cell type, TPCS 2a yielded higher fluorescence in all cell types compared to TPPS 2a at the same doses. This is in line with studies that have also examined uptake of both photosensitisers ( Martinez De Pinillos Bayona et al, 2017 ). However since TPCS 2a is a more efficient fluorophore than TPPS 2a , the higher intracellular fluorescence does not imply that higher concentrations of TPCS 2a are taken up by cells ( Lilletvedt et al, 2010 ).…”

Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

“…These PCI results compare favourably with those obtained with analogous N- and C-terminal Tat conjugates bearing a highly hydrophobic tetraphenylporphine moiety 28 and the disulfonated tetraphenylporphine derivative 46 . Comparing the alpha values calculated using equation 1 (Methods) to ascertain whether a synergistic effect is observed, alpha values of 6.2 and 4.4 are obtained for 7 and 8, which is consistent with a synergistic effect (ie alpha greater than unity) attributable to PCI.…”

“…If α > 1 then a synergistic effect has been observed whereas an antagonistic effect is denoted by α < 1. This analysis has been used previously by us and others to identify synergistic effects in PCI 46 , 52 .…”

Codelivery of a cytotoxin and photosensitiserviaa liposomal nanocarrier: a novel strategy for light-triggered cytosolic release

“…When the viability measurements were carried out at 48 h (Fig. 6) after light treatment instead of 96 h, a synergistic PCI effect was also observed, albeit with lower α values: codelivery of 100 nM TPP and 11.4 nM saporin with an illumination time of 3 min gave 3.4 for α compared to 8 at 96 h. The PCI-induced reduction in viability was also lower at 48 h. The higher efficacy observed at 96 h compared to 48 h reflects the slower onset of the cytotoxic action of released saporin via apoptosis and is consistent with our own previous results61 and other PCI studies 62…”