CoChat
Sign Up
Cited by 11Photodynamic Therapy Research StudiesPorphyrin Metabolism and DisordersPorphyrin and Phthalocyanine Chemistry

Experimental investigation of a combinational iron chelating protoporphyrin IX prodrug for fluorescence detection and photodynamic therapy

Open access
Magnussen, Anette, Reburn, Charlotte, Perry, Alexis, Wood, Mark, Curnow, Alison·2022·Lasers in Medical Science
DOI 10.1007/s10103-021-03367-1PMC PMC8918167
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s10103-021-03367-1

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [101]

    The Discussion (page unavailable) says AP2-18 was equally as effective as separate co-administration in bladder cells, and reports greater PpIX accumulation with AP2-18 in skin cancer cells. But it also says neither AP2-18 nor separate CP94 meaningfully enhanced bladder-cell fluorescence or PDT cell death, so the claim that AP2-18 increases both outcomes across different cell lines is too broad. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 46 · Cited by 11

Research works printed but not linked: 36

  1. [2]Taylor EL Brown SB The advantages of aminolevulinic acid photodynamic therapy in dermatology J Dermatol Treat 2002 13 S3 11 12060511
  2. [3]Wong TH Morton CA Collier N Haylett A Ibbotson S McKenna KE BAD & BPG Guidelines for Topical PDT Br J Dermatol 2019 180 730 739 30506819
  3. [4]Morton C Szeimies R Sidoroff A Braathen L European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications - actinic keratoses, Bowen’s disease, basal cell carcinoma JEADV 2013 27 536 544 23181594
  4. [5]Dirschka T Radny P Dominicus R Mensing H Brüning H Jenne L Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo Br J Dermatol 2012 166 137 146 21910711
  5. [6]Del Duca E Manfredini M Petrini N Farnetani F Chester J Bennardo L Daylight photodynamic therapy with 5-aminolevulinic acid 5% gel for the treatment of mild-to-moderate inflammatory acne G Ital Dermatol Venereol 2021 2021 156 46 50 31525842
  6. [7]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
  7. [8]Annemans L Caekelbergh K Roelandts R Boonen H Leys C Nikkels A van Den Haute V van Quickenborne L Verhaeghe E Leroy B Real-life practice study of the clinical outcome and cost-effectiveness of photodynamic therapy using methyl aminolevulinate (MAL-PDT) in the management of actinic keratosis and basal cell carcinoma Euro J Derm 2008 18 539 546 18693157
  8. [9]Basset-Seguin N Ibbotson S Emtestam L Tarstedt M Morton C Maroti M Calzavara-Pinton P Varma S Roelandts R Wolf P Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial Euro J Derm 2008 18 547 553 18693158
  9. [10]Morton C Horn M Leman J Tack B Bedane C Tijoe M Ibbotson S Khemis A Wolf P Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: results of a multicenter randomized trial Arch Derm 2006 142 729 735 16785375
  10. [11]Hanania J Malik Z The effect of EDTA and serum on endogenous porphyrin accumulation and photodynamic sensitization of human K562 leukemic cells Cancer Let 1992 65 127 131 1511416
  11. [12]Liu H Xu S Zhang C Influence of CaNa2 EDTA on topical 5-aminolaevulinic acid photodynamic therapy Chin Med J (English) 2004 117 922 926 15198900
  12. [13]Malik Z Kostenich G Roitman L Ehrenberg B Orenstein A Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice J Photochem Photobiol B: Biol 1995 28 213 218 7623186
  13. [14]Fayter D Corbett M Heirs M Fox D Eastwood A A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett’s oesphagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin Health Technol Assess 2010 14 1 288 20663420
  14. [15]Lange N Jichlinski P Zellweger M Forrer M Marti A Guillou L Kucera P Wagnières G van den Bergh H Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: a pilot study Br J Cancer 1999 80 185 193 10389995 PMC2363006
  15. [16]Kriegmair M Zaak D Knuechel R Baumgartner R Hofstetter A 5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower urinary tract tumors Urol Int 1999 63 27 31 10592487
  16. [17]Kriegmair M Zaak D Stepp H Stepp H Baumgartner R Knuechel R Hofstetter A Transurethral resection and surveillance of bladder cancer supported by 5-aminolevulinic acid-induced fluorescence endoscopy Eur Urol 1999 36 386 392 10516447
  17. [18]Markwardt N Markwardt N Haj-Hosseini N Hollnburger B Stepp H Zelenkov P Rühm A 405 nm versus 633 nm for protoporphyrin IX excitation in fluorescence-guided stereotactic biopsy of brain tumors J Biophotonics 2016 9 901 912 26564058
  18. [19]Wennberg A Gudmundson F Stenquist B Ternesten A Molne L Rosen A In vivo detection of basal cell carcinoma using imaging spectroscopy Acta Derm Venereol 1999 79 54 61 10086861
  19. [20]De Rosa F Tedesco A Lopez R Pierre M Lange N Marchetti J Rotta J Bentley M In vitro skin permeation and retention of 5-aminolevulinic acid ester derivatives for photodynamic therapy J Control Release 2003 89 261 269 12711449
  20. [21]Krieg R Uihlein D Murthum T Endlicher E Hausmann F Messmann H Knuechel R Improving the use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) for the gastrointestinal tract by esterification—an in vitro study Cell Mol Biol (Noisy-le-grand) 2002 48 917 23 12699251
  21. [22]Bader M Stepp H Beyer W Pongratz T Sroka R Kriegmair M Zaak D Welschof M Tilki D Stief C Waidelich R Photodynamic therapy of bladder cancer—a phase I study using hexaminolevulinate (HAL) Urol Oncol 2013 31 1178 1183 22440147
  22. [24]Di Stasi S De Carlo F Pagliarulo V Masedu F Verri C Celestino F Riedl C Hexaminolevulinate hydrochloride in the detection of nonmuscle invasive cancer of the bladder Ther Adv Urol 2015 7 339 350 26622319 PMC4647142
  23. [25]Blake E Curnow A The hydroxypyridinone iron chelator CP94 can enhance PpIX-induced PDT of cultured human glioma cells Photochem Photobiol 2010 86 1154 1160 20573043
  24. [26]Blake E Allen J Curnow A The effects of protoporphyrin IX-induced photodynamic therapy with and without iron chelation on human squamous carcinoma cells cultured under normoxic, hypoxic and hyperoxic conditions Photodiagnosis Photodyn Ther 2013 10 575 582 24284114
  25. [28]Campbell S Morton C Alyahya R Horton S Pye A Curnow A Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma Br J Dermatol 2008 159 387 393 18544077
  26. [32]Battah S Hider R MacRobert A Dobbin P Zhou T Hydroxypyridinone and 5-aminolaevulinic acid conjugates for Photodynamic Therapy J Med Chem 2017 60 3498 3510 28363026
  27. [33]Zhou T Battah S Mazzacuva F Hider R Dobbin P MacRobert A Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy Bioconjug Chem 2018 29 3411 3428 30249090
  28. [36]Repetto G del Peso A Zurita J Neutral red uptake assay for the estimation of cell viability/cytotoxicity Nat Protoc 2008 3 1125 1131 18600217
  29. [37]Rossi M Masters J Park S Todd J Garrett S Sens M Somji S Nath J Sens D The immortalized UROtsa cell line as a potential cell culture model of human urothelium Environ Health Perspect 2001 109 801 808 11564615 PMC1240407
  30. [38]Krieg R Fickweiler S Wolfbeis O Knuechel R Cell-type specific protoporphyrin IX metabolism in human bladder cancer in vitro Photochem Photobiol 2000 72 226 233 10946577
  31. [39]Seidl J Rauch J Krieg R Appel S Baumgartner R Knuechel R Optimization of differential photodynamic effectiveness between normal and tumor urothelial cells using 5-aminolevulinic acid-induced protoporphyrin IX as sensitizer Int J Cancer 2001 92 671 677 11340570
  32. [40]Hider R Kong X Iron speciation in the cytosol: an overview Dalton Trans 2013 42 3220 3229 23232973
  33. [43]Akan P Alexeyenko A Costea P Hedberg L Solnestam B Lundin S Hällman J Lundberg E Uhlén M Lundeberg J Comprehensive analysis of the genome transcriptome and proteome landscapes of three tumor cell lines Genome Med 2012 4 86 23158748 PMC3580420
  34. [44]Chan F Moriwaki K De Rosa M Detection of necrosis by release of lactate dehydrogenase activity Methods Mol Biol 2013 979 65 70 23397389 PMC3763497
  35. [45]Datta S Allman R Loh C Mason M Matthews P Photodynamic therapy of bladder cancer cell lines Br J Urol 1997 80 421 426 9313661
  36. [46]Sun J Zhang D Zheng Y Zhao Q Zheng M Kovacevic Z Richardson D Targeting the metastasis suppressor, NDRG1, using novel iron chelators: regulation of stress fiber-mediated tumor cell migration via modulation of the ROCK1/pMLC2 signaling pathway Mol Pharmacol 2013 83 454 469 23188716

Authors
Magnussen, A., Reburn, C., Perry, A., Wood, M., & Curnow, A.
Affiliations
University of Exeter (GB)
Corresponding author
Curnow, Alison
ORCID
Venue
Lasers in Medical Science
Publisher
Springer Science and Business Media LLC
Published
2021-07-04
Volume
37
Issue
2
Pages
1155-1166
ISSN
  • 0268-8921 (ISSN-L)
  • 1435-604X
DOI
10.1007/s10103-021-03367-1
PMC
PMC8918167
OpenAlex
W3180898952
Cited by
11
References
46
Citations by year
2026: 3 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 1
FWCI
1.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Lasers in Medical Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
Funders
  • Medical Research Council UK
  • Killing Cancer UK
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, prodrugs, 5-aminolevulinic acid, heme biosynthesis, photosensitizers, bladder cancer cells, squamous cell carcinoma, actin cytoskeleton, apoptosis, caspase-3, fluorescence detection
MeSH terms
Aminolevulinic Acid, Fluorescence, Humans, Iron Chelating Agents, Photochemotherapy, Prodrugs, Protoporphyrins, Photosensitizing Agents

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review