The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy

Curnow, Alison; Pye, A. Kenneth

doi:10.1515/plm-2014-0034

Cited by 12 publications

(21 citation statements)

References 58 publications

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“…a and b). This supports our previous findings where MAL‐treated cells accumulated less PpIX than cells treated with the same concentration of ALA . Furthermore the cytotoxicity findings of cell death quantified with the LDH assay (Figs.…”

Section: Discussionsupporting

confidence: 91%

“…This suggests that the iron chelator CP94 is most effective in the cancer cells where the haem biosynthesis pathway is more likely to be disrupted . These findings support several studies that found that the addition of an iron chelator to a PpIX precursor increased PpIX accumulation and therefore fluorescence before irradiation , with MAL + CP94 treated cells producing the greatest enhancement of PpIX fluorescence in tumor cells . This occurs because iron chelating agents reduce cellular levels of free iron, which is essential for haem formation to take place and thus this change in cellular environment, forces more PpIX to accumulate in the cell .…”

Section: Discussionsupporting

confidence: 79%

“…Concurrent administration of an iron chelator during PpIX‐PDT has also been demonstrated to increase cellular accumulation of PpIX . This approach works because once the PpIX has bound Fe 2+ to form haem, it is no longer active for PDT and so by adding iron chelators to trap iron ions in combination with PpIX precursors, this competition can be undermined elevating PpIX accumulation and thus increasing cell kill on subsequent irradiation . Iron chelation has now been reported as a method of enhancing PpIX‐induced PDT using the iron chelating agents, ethylenediamine tetraacetic acid (EDTA) , desferrioxamine (DFO; Desferal, Novartis) and the novel hydroxypyridinone iron chelator CP94 .…”

Section: Introductionmentioning

confidence: 99%

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An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy

et al. 2018

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ObjectivesNon‐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.MethodsHuman 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.ResultsGenerally, 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 co‐administration 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.ConclusionsPpIX 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 synthesized 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 the potential to improve dermatological PDT outcomes in applications currently requiring enhancement. Lasers Surg. Med. 50:552–565, 2018. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy

et al. 2018

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“…Previous experimental work undertaken with cultured human cells in an iron controlled/standardised environment has suggested however, that the role of limited iron levels in elevating PpIX accumulation has a greater effect on the level of cellular damage produced by PpIX-induced PDT than the role of excess iron availability in the formation of ROS (as the level of damage/death was related to the differences in the accumulation of PpIX observed) [49]. A possible explanation for this may be that other transition metals (such as zinc or copper) may be able to mediate Fenton-type reactions instead of iron in the ROS cascades triggered by PpIX-PDT.…”

Section: Discussionmentioning

confidence: 97%

Enhancing Protoporphyrin IX induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model

Curnow¹,

Macrobert²

2016

J Heavy Met Toxicity Dis

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Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being utilised within dermatological practice as a topical method of localised ablation of nonmelanoma skin cancer/precancer. Standardised protocols have been implemented to good effect when the disease remains superficial but improvement is required to widen the application of this light activated drug therapy to treat thicker or acrally located conditions. As innate haem biosynthesis is exploited to accumulate the light sensitive PpIX from a topically applied inert prodrug (aminolaevulinic acid; ALA), this pathway can be further manipulated through the concurrent administration of an iron chelating agent to hyper-accumulate PpIX by temporarily reducing its iron dependent conversion to haem.A topical preparation of ALA was applied to normal rat skin with or without the hydroxypyridinone iron chelator, CP94. Image analysis quantification of tissue fluorescence following excision indicated that ALA plus CP94 produced 29.0% more fluorescence than ALA alone (p < 0.09), peaking at 5 hours. Furthermore, fluorescence spectroscopy of frozen skin samples from each treatment group were characteristic of PpIX (maxima 636 +/-2 nm), indicating that topical CP94 administration elevated PpIX levels without significantly producing any other fluorescent species. When PDT efficacy was considered post irradiation, a substantial three-fold increase in effect was observed 4 days after treatment when the iron chelator CP94 was co-administered topically with the prodrug (p < 0.07).It has therefore been established that the hydroxypyridinone CP94, is topically active within normal rat skin, effectively chelating iron to elevate PpIX accumulation and thus improve PDT efficacy.4

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“…Alison Curnow and Andrew Pye [18] show that the efficacy of 5-ALA-PDT is enhanced by reducing the availability of the iron required to convert PpIX to haem, which outweighs the reduction in cytotoxicity related to less ROS activation. The number of ROS per cell produced during PDT is the key value which determines the fate of the cell.…”

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confidence: 99%

Photodynamic diagnosis and therapy – How bright is the future?

Bown

Stepp²

2015

Photonics &Amp; Lasers in Medicine

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The importance of iron chelation and iron availability during PpIX-induced photodynamic therapy

Abstract: Background: Protoporphyrin IX (PpIX)-induced photodynamic therapy (PDT) is being

Cited by 12 publications

References 58 publications

An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy

An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy

Enhancing Protoporphyrin IX induced Photodynamic Therapy with a Topical Iron Chelating Agent in a Normal Skin Model

Photodynamic diagnosis and therapy – How bright is the future?

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