Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Curnow, Alison; Perry, Alexis; Wood, Mark E.

doi:10.1016/j.pdpdt.2018.12.005

Cited by 18 publications

(18 citation statements)

References 65 publications

(129 reference statements)

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“…This is particularly important as CP94 is already in the public domain, which means it cannot be protected in a secure manner for clinical development. The new combined PpIX‐precursor and siderophore, AP2‐18 has therefore been specifically developed for this application and its synthesis patented to resolve this issue, so that the enhancement of PpIX‐induced PDT via iron chelation can be developed clinically for patient benefit.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…A more recent development in this field has been the design and synthesis of a new iron chelating PpIX prodrug, AP2‐18 (Patent: Curnow, Wood & Perry; 06/03/14; PCT/GB2013/052297) . This experimental drug essentially ester links ALA to CP94 to aid their co‐delivery to cells in equimolar amounts.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Recent innovations exploiting this need for iron include the development of an ester prodrug that combines 5-ALA with the iron chelator, CP94. 52 Further studies will determine whether strategies such as iron chelation will be effective in vivo for the diagnosis and treatment of cancer with 5-ALA.…”

Section: Role Of Iron In Ferrochelatase Regulation In Cancermentioning

confidence: 99%

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

2019

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Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.

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“…Membrane penetration, as a first factor determining the amount of PpIX that accumulates in cancer cells, is expected to play an important role for cells suspended in body fluids due to the increase in membrane area exposed to the prodrug for uptake. The accumulation of PpIX is subsequently dictated by a sequence of enzymatic reactions, including iron chelation [24,25]. Thus, we hypothesise that HAL-induced cancer specific fluorescence could be altered by the addition of chemical adjuvants acting either on membrane permeability or enzymatic conversion rate.…”

Section: Introductionmentioning

confidence: 99%

“…The accumulation of PpIX is subsequently dictated by a sequence of enzymatic reactions, including iron chelation [24,25]. Thus, we hypothesise that HAL-induced cancer specific fluorescence could be altered by the addition of chemical adjuvants acting either on membrane permeability or enzymatic conversion rate.…”

Section: Introductionmentioning

confidence: 99%

Probing Hexaminolevulinate Mediated PpIX Fluorescence in Cancer Cell Suspensions in the Presence of Chemical Adjuvants

Chan

Gleadle

Vasilev

et al. 2020

IJMS

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Exogenous administration of hexaminolevulinate (HAL) induces fluorescent protoporphyrin IX (PpIX) accumulation preferentially in cancer cells. However, the PpIX fluorescence intensities between noncancer and cancer cells are highly variable. The contrast between cancer and noncancer cells may be insufficient to reliably discriminate, especially at the single cell level in cancer diagnostics. This study examines the use of the chemical adjuvants dimethylsulphoxide (DMSO) or deferoxamine (DFO) to enhance the HAL induced PpIX accumulation in cancer cells. Our results showed that in some of the incubation conditions tested, the addition of DFO with HAL significantly increased PpIX 21 fluorescence of adherent monolayer cancer cells, but this was never the case for cells in suspension. Permeabilisation with DMSO did not increase PpIX fluorescence. Cell-to-cell interaction may well play an important role in the PpIX accumulation when suspended cells are treated in HAL and adjuvant chemicals.presence of intracellular PpIX. 5-ALA based PDD is used in the detection of a wide range of cancers, such as brain [5], ovarian [6], colorectal [7], breast [8] and bladder [9]. In urology, blue light cystoscopy PPD is now recommended by several guidelines around the world. Yet the underlying mechanisms responsible for the specificity of PpIX accumulation in tumour cells remains poorly understood [10]. To date, it has been attributed to the distinctive nature of cancer cells, primarily, to reduced FECH activity [11] and to the limited availability of iron in cancer cells [12,13] or to the reduced availability of nicotinamide adenine dinucleotide phosphate (NADPH) provision. However, the difference in PpIX fluorescence intensity between normal and cancer cells is highly variable from one cell type to another [14]. In fact, the contrast is, in some cases, insufficient to reliably discriminate between the two, especially when applying PDD principles ex vivo, at the single cell level [15,16]. To enable the development of noninvasive diagnostic methods using PDD on body fluid sediments, such as urine [17][18][19][20], practical ways to enhance the PpIX fluorescence contrast ex vivo are required [21]. Strategies to do so may well be different from those that are successful in vivo, simply because the cell microenvironments are drastically different in those two scenarios.

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Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug

Abstract: Graphical abstract

Cited by 18 publications

References 65 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

In order for the light to shine so brightly, the darkness must be present—why do cancers fluoresce with 5-aminolaevulinic acid?

Probing Hexaminolevulinate Mediated PpIX Fluorescence in Cancer Cell Suspensions in the Presence of Chemical Adjuvants

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