Abstract
Photodynamic therapy (PDT) is an oxygen-dependent, light-activated, and locally destructive drug treatment of cancer. Protoporphyrin IX (PpIX)-induced PDT exploits cancer cells’ own innate heme biosynthesis to hyper-accumulate the naturally fluorescent and photoactive precursor to heme, PpIX. This occurs as a result of administering heme precursors (e.g., aminolevulinic acid; ALA) because the final step of the pathway (the insertion of ferrous iron into PpIX by ferrochelatase to form heme) is relatively slow. Separate administration of an iron chelating agent has previously been demonstrated to significantly improve dermatological PpIX-PDT by further limiting heme production. A newly synthesized combinational iron chelating PpIX prodrug (AP2-18) has been assessed experimentally in cultured primary human cells of bladder and dermatological origin, as an alternative photosensitizing agent to ALA or its methyl or hexyl esters (MAL and HAL respectively) for photodetection/PDT. Findings indicated that the technique of iron chelation (either through the separate administration of the established hydroxypyridinone iron chelator CP94 or the just as effective combined AP2-18) did not enhance either PpIX fluorescence or PDT-induced (neutral red assessed) cell death in human primary normal and malignant bladder cells. However, 500 µM AP2-18 significantly increased PpIX accumulation and produced a trend of increased cell death within epithelial squamous carcinoma cells. PpIX accumulation destabilized the actin cytoskeleton in bladder cancer cells prior to PDT and resulted in caspase-3 cleavage/early apoptosis afterwards. AP2-18 iron chelation should continue to be investigated for the enhancement of dermatological PpIX-PDT applications but not bladder photodetection/PDT.
Highlights
Photodynamic therapy (PDT) is based on the activation of a photosensitizer by visible light and the transfer of energy to molecular oxygen, creating reactive oxygen species (ROS) that induce oxidative stress and cell death [1]. 5-Aminolevulinic acid (ALA)-induced-PDT exploits the cell’s own innate heme biosynthesis pathway to generate the natural endogenous photosensitizer protoporphyrin IX (PpIX; the precursor to heme)
Near linear Protoporphyrin IX (PpIX) fluorescence was produced up to 6 h in all cases by AP2-18 in the RT-112 bladder cancer cells evaluated with ALA or HAL incubated with an equimolar amount of the iron chelator CP94 (Fig. 1d–f)
The same observation was made when RT-112 cells were treated with HAL + CP94, where the highest fluorescence levels were reached with 250 μM (Fig. 1e)
Summary
Photodynamic therapy (PDT) is based on the activation of a photosensitizer by visible light and the transfer of energy to molecular oxygen, creating reactive oxygen species (ROS) that induce oxidative stress and cell death [1]. 5-Aminolevulinic acid (ALA)-induced-PDT exploits the cell’s own innate heme biosynthesis pathway to generate the natural endogenous photosensitizer protoporphyrin IX (PpIX; the precursor to heme). 5-Aminolevulinic acid (ALA)-induced-PDT exploits the cell’s own innate heme biosynthesis pathway to generate the natural endogenous photosensitizer protoporphyrin IX (PpIX; the precursor to heme). Cellular accumulation of PpIX occurs as the final step (the insertion of ferrous iron ( Fe2+) into PpIX by ferrocheletase to form heme) is relatively slow [1]. This process occurs at a faster rate in malignant cells (which generally have upregulated and less well controlled heme biosynthesis) than in normal cells and so a temporally selective window occurs when red light (635 nm) can be applied to activate PpIX within the tumor, while sparing surrounding normal cells [1]. There is interest in applying PDT beyond dermatology, in a wide range of oncological/non-oncological applications [14]
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