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Cited by 19Photodynamic Therapy Research StudiesPorphyrin Metabolism and DisordersPorphyrin and Phthalocyanine Chemistry

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

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Anayo, Lizette, Magnussen, Anette, Perry, Alexis, Wood, Mark, Curnow, Alison·2018·Lasers in Surgery and Medicine
DOI 10.1002/lsm.22809PMC PMC6032951
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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 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 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. 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 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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  • Multiple studies indicate that AP2-18 increases ALA-PpIX fluorescence and PDT as effectively as ALA and CP94 co-administered separately.

    “Multiple studies with different cell lines indicate that AP2-18 increases ALA-PpIX fluorescence and PDT as effectively as ALA and CP94 co-administered separately [99,100,101].”

    From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [99]

    The Results section reports that AP2-18 increased PpIX fluorescence in both cell lines and that its fluorescence in A431 cells did not differ significantly from separately administered ALA + CP94. PDT effectiveness was not consistently comparable: at 500 μM, AP2-18 caused significantly less cell death than ALA + CP94 in A431 cells, although it caused more in normal fibroblasts. Page numbers were not available in our copy. (LLM, conf=0.88)

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  1. [33]Tyrrell J, Morton C, Campbell S, Curnow A. Comparison of PpIX accumulation and destruction during methyl‐aminolevulinate photodynamic therapy (MAL‐PDT) of skin tumours located at acral and non‐acral sites. Br J Dermatol 2011; 164: 1362– 1368. 21564050

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Authors
Anayo, L., Magnussen, A., Perry, A., Wood, M., & Curnow, A.
Affiliations
University of Exeter (GB)
Corresponding author
Curnow, Alison
ORCID
Venue
Lasers in Surgery and Medicine
Publisher
Wiley
Published
2018-03-31
Volume
50
Issue
5
Pages
552-565
ISSN
  • 0196-8092 (ISSN-L)
  • 1096-9101
DOI
10.1002/lsm.22809
PMC
PMC6032951
OpenAlex
W2806491388
Cited by
19
References
81
Citations by year
2026: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 2
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Lasers in Surgery and Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open Research Exeter (University of Exeter) (submittedVersion, public-domain)
  • Figshare (submittedVersion)
Funders
Medical Research Council
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
  • Physical Sciences › Materials Science › Materials Chemistry › Porphyrin and Phthalocyanine Chemistry
Keywords
protoporphyrin IX, photodynamic therapy, iron chelation, 5-aminolevulinic acid, methyl aminolevulinate, non-melanoma skin cancer, photosensitizer accumulation, squamous cell carcinoma
MeSH terms
Carcinoma, Squamous Cell, Epithelial Cells, Fibroblasts, Humans, Iron Chelating Agents, Photochemotherapy, Prodrugs, Protoporphyrins, Pyridones, Skin Neoplasms, Photosensitizing Agents, Cell Culture Techniques

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