Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid

Curnow, Alison; MacRobert, Alexander J.; Bown, Stephen G.

doi:10.1002/lsm.20328

Cited by 36 publications

(30 citation statements)

References 40 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many adaptations to standard treatment have been considered to improve efficacy including skin pre-treatment with the malignant cell differentiation potentiator dimethyl sulfoxide [20], skin stripping with tape [21], light dose fractionation [22,23], low fluence rate light administration [24] as well as combinations with other techniques such as low-dose Photofrin ® [25], hyperthermia [26,27], iontophoresis [28] and bioreductive drugs [29]. Concurrent administration of an iron chelator, such as ethylenediamine tetraacetic acid (EDTA) [30][31][32][33], desferrioxamine (DFO) [30,[34][35][36][37] or the novel hydroxypyridinone iron chelator 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94) [38][39][40][41][42][43], during PpIX-PDT has also been demonstrated to increase cellular accumulation of PpIX by reducing its bioconversion to haem by ferrochelatase (an iron dependent process) thus increasing cell kill on subsequent irradiation. This method of enhancement is attractive because simply increasing the precursor dose or application time doesn't appear to produce cost efficacy or practical substantial improvements [44].…”

Section: Introductionmentioning

confidence: 99%

“…CP94 is particularly effective at chelating intracellular iron and has a lower molecular weight and higher lipophilicity than either DFO or EDTA [45] and is well suited to augmenting dermatological PDT as it can be applied topically [46]. CP94 has already been demonstrated to enhance ALA-induced PpIX fluorescence [38] and to also produce greater tumour necrosis within animal models [41,42].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Curnow

Pye

2015

Photonics &Amp; Lasers in Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Curnow

Pye

2015

Photonics &Amp; Lasers in Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore it was hypothesized that exposing cells to a hyperoxic environment prior to, and post light irradiation, would address these issues and have an effect on the amount of PpIX photobleaching measured and subsequently the level of cell ablation observed. The only previous study where both iron chelation with CP94 and oxygen manipulation was studied in conjunction PpIX-induced PDT found that light dose fractionation and CP94 were both equally effective methods of enhancing ALA-PDT in normal rat colon and furthermore that the techniques were not mutually exclusive and could therefore be combined to produce even greater treatment effects [44]. In this study, the level of PpIX photobleaching observed ( Figure 2) was increased when each prodrug was coincubated with CP94, and this was attributed to the increased accumulation of PpIX observed preirradiation.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Iron Chelation and Hypoxic or Hyperoxic Oxygen Manipulation on the Accumulation/Photobleaching of Protoporphryin IX and Cytotoxcity in Human Glioma Cells

Blake¹,

Allen²,

Curnow³

2013

J Anal Bioanal Tech

View full text Add to dashboard Cite

Background and objective: Gliomas remain the most common and problematic primary brain tumors to treat given their mobile and invasive characteristics, resulting in a 5 years survival rate of less than 5%. Recently the administration of photosensitive fluorescent drugs has been utilized to aid in the identification and resection of gliomas. In this experimental investigation of human glioma cells the effect of iron chelation and oxygenation manipulation, firstly on the accumulation of the clinically useful photosensitizer protoporphyrin IX (PpIX) and subsequently on PpIX photobleaching and cytotoxicity on irradiation, has been examined with the aim of improving fluorescence-guided resection/photodynamic therapy (PDT). Materials and methods:Cells were incubated at concentrations of 5%, 20% or 40% oxygen for 24 hours prior to and for 3 hours following the administration of the PpIX precursors aminolevulinic acid (ALA), methyl levulinate (MAL) or hexyl aminolevulinate (HAL) with or without the iron chelator 1,2-diethyl-3-hydroxypyridin-4-one hydrochloride (CP94). PpIX levels were monitored using a fluorescence plate reader (excitation filter 400 ± 30 nm; emission filter 645 ± 40 nm). Cells were irradiated with 15 J/cm 2 red lights and viability measured using the neutral red uptake assay.Results: Manipulation of the oxygen environment and/or co administration of CP94 with PpIX precursors resulted in significant changes in both PpIX accumulation and photobleaching. Incubation with ALA/ MAL at 5% or 40% oxygen produced the greatest levels of PpIX and photobleaching respectively. Both these parameters were further elevated through co administration of CP94. The combination of hyperoxygenation and CP94 administration significantly increased photobleaching (a marker of PDT effect) but not cytotoxicity in this experimental system. Conclusions:PpIX accumulation was greatest when the cells were grown in hypoxic (5% oxygen) conditions (mimicking the in vivo situation) with ALA/MAL+CP94. Fluorescence-guided resection of glioma may therefore be improved through the addition of the iron chelating adjuvant CP94.

show abstract

“…This experimentation has been extended here to consider the effect of topical CP94 administration in vivo in a normal rat skin model. In light of our previous findings with CP94 augmentation of PpIX-PDT demonstrated in epidermal squamous carcinoma cells (A431) [30][31], a colonic tumour model [33] and dermatological skin lesions [35][36], it was not deemed necessary to create a neoplastic skin model here when our main focus was to assess PpIX production/excised tissue fluorescence (which we have been unable to do clinically due to ethical constraints).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, CP94 has been utilised intravenously to enhance ALAinduced PpIX fluorescence and necrosis in the normal rat colon [32] and to also produce greater tumour necrosis within a colonic rat tumour model [33]. However because CP94 experiences rapid first pass glucuronidation when administered orally to humans [34], a topical administration route for a dermatological PDT application may be preferable.…”

Section: Introductionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with aminolevulinic acid

Cited by 36 publications

References 40 publications

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

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

The Effects of Iron Chelation and Hypoxic or Hyperoxic Oxygen Manipulation on the Accumulation/Photobleaching of Protoporphryin IX and Cytotoxcity in Human Glioma Cells

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

Contact Info

Product

Resources

About