An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy (article)
Anayo, L; Magnussen, A; Perry, A; et al.Wood, M; Curnow, A
Date: 31 March 2018
Article
Journal
Lasers in Surgery and Medicine
Publisher
Wiley
Publisher DOI
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Abstract
Objectives: Non-melanoma skin cancers are the most frequently occurring type of cancer
worldwide. They can be effectively treated using topical dermatological photodynamic therapy
(PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease
remains superficial. Novel iron chelating agents are ...
Objectives: Non-melanoma skin cancers are the most frequently occurring type of cancer
worldwide. They can be effectively treated using topical dermatological photodynamic therapy
(PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease
remains superficial. Novel iron chelating agents are being investigated to enhance the effectiveness
and extend the applications of this treatment modality, as limiting free iron increases the
accumulation of PpIX available for light activation and thus cell kill.
Methods: Human lung fibroblasts (MRC-5) and epithelial squamous carcinoma (A431) cells were
treated with PpIX precursors (aminolaevulinic acid (ALA) or methyl-aminolevulinate (MAL)) with or
without the separate hydroxypyridinone iron chelating agent (CP94) or alternatively, the new
combined iron chelator and PpIX producing agent, AP2-18. PpIX fluorescence was monitored hourly
for 6 hours prior to irradiation. PDT effectiveness was then assessed the following day using the
lactate dehydrogenase and neutral red assays.
Results: Generally, iron chelation achieved via CP94 or AP2-18 administration significantly increased
PpIX fluorescence. ALA was more effective as a PpIX-prodrug than MAL in A431 cells, corresponding
with the lower PpIX accumulation observed with the latter congener in this cell type. Addition of
either iron chelating agent consistently increased PpIX accumulation but did not always convey an
extra beneficial effect on PpIX-PDT cell kill when using the already highly effective higher dose of
ALA. However, these adjuvants were highly beneficial in the skin cancer cells when compared with
MAL administration alone. AP2-18 was also at least as effective as CP94 + ALA/MAL coadministration
throughout and significantly better than CP94 supplementation at increasing PpIX
fluorescence in MRC5 cells as well as at lower doses where PpIX accumulation was observed to be
more limited.
Conclusions: PpIX fluorescence levels, as well as PDT cell kill effects on irradiation can be
significantly increased by pyridinone iron chelation, either via the addition of CP94 to the
administration of a PpIX precursor or alternatively via the newly synthesised combined PpIX prodrug
and siderophore, AP2-18. The effect of the latter compound appears to be at least equivalent to, if
not better than, the separate administration of its constituent parts, particularly when employing
MAL to destroy skin cancer cells. AP2-18 therefore warrants further detailed analysis, as it may have
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the potential to improve dermatological PDT outcomes in applications currently requiring
enhancement.
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