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Vol. 218, No. 3, 2009
Issue release date: February 2009
Dermatology 2009;218:193–202

Pretreatment to Enhance Protoporphyrin IX Accumulation in Photodynamic Therapy

Gerritsen M.J.P. · Smits T. · Kleinpenning M.M. · van de Kerkhof P.C.M. · van Erp P.E.J.
Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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The response rates of photodynamic therapy (PDT) vary widely. Limited uptake of topically applied 5-aminolaevulinic acid (ALA), or its methyl ester (MAL), and suboptimal production of protoporphyrin IX (PpIX) may account for these differences. Recently, we demonstrated that hyperkeratosis is an important negative factor in ALA uptake. This review has its focus on pretreatment of the skin in order to improve the clinical outcome of ALA/MAL PDT. Pretreatment of hyperkeratosis can be achieved with keratolytics, curettage/debulking, tape stripping, microdermabrasion or laser ablation. Penetration enhancers may alter the composition or organization of the intercellular lipids of the stratum corneum. Several studies have been performed on the use of dimethyl sulfoxide, azone, glycolic acid, oleic acid and iontophoresis to increase the penetration of ALA. As PpIX production is also dominated by temperature-dependent processes, elevating skin temperature during ALA application may also improve treatment results. Another approach is the use of additives that interact with the heme biosynthetic pathway, e.g. by removing ferrous iron with iron-chelating substances such as: ethylenediaminetetraacetic acid; 3-hydroxypyridin-4-ones; 1,2-diethyl-3-hydroxypyridin-4-one-hydrochloride; and desferrioxamine. In conclusion, simple pretreatments or additions to the regular practice of PDT, aimed to optimize intralesional PpIX content, improve the clinical outcome.

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  1. Kleinpenning MM, Smits T, Ewalds E, van Erp PE, van de Kerkhof PC, Gerritsen MJ: Heterogeneity of fluorescence in psoriasis after application of 5-aminolaevulinic acid: an immunohistochemical study. Br J Dermatol 2006;155:539–545.
  2. Smits T, Kleinpenning MM, Blokx WA, van de Kerkhof PC, van Erp PE, Gerritsen MJ: Fluorescence diagnosis in keratinocytic intraepidermal neoplasias. J Am Acad Dermatol 2007;57:824–831.
  3. Smits T, Robles CA, van Erp PE, van de Kerkhof PC, Gerritsen MJ: Correlation between macroscopic fluorescence and protoporphyrin IX content in psoriasis and actinic keratosis following application of aminolevulinic acid. J Invest Dermatol 2005;125:833– 839.
  4. Ibbotson SH, Jong C, Lesar A, et al: Characteristics of 5-aminolaevulinic acid-induced protoporphyrin IX fluorescence in human skin in vivo. Photodermatol Photoimmunol Photomed 2006;22:105–110.
  5. Katz BE, Truong S, Maiwald DC, Frew KE, George D: Efficacy of microdermabrasion preceding ALA application in reducing the incubation time of ALA in laser PDT. J Drugs Dermatol 2007;6:140–142.

    External Resources

  6. Shen SC, Lee WR, Fang YP, Hu CH, Fang JY: In vitro percutaneous absorption and in vivo protoporphyrin IX accumulation in skin and tumors after topical 5-aminolevulinic acid application with enhancement using an erbium:YAG laser. J Pharm Sci 2006;95:929–938.
  7. Souza CS, Neves AB, Felicio LA, Ferreira J, Kurachi C, Bagnato VS: Optimized photodynamic therapy with systemic photosensitizer following debulking technique for nonmelanoma skin cancers. Dermatol Surg 2007;33:194–198.
  8. Thissen MR, Schroeter CA, Neumann HA: Photodynamic therapy with delta-aminolaevulinic acid for nodular basal cell carcinomas using a prior debulking technique. Br J Dermatol 2000;142:338–339.
  9. Berroeta L, Clark C, Dawe RS, Ibbotson SH, Fleming CJ: A randomized study of minimal curettage followed by topical photodynamic therapy compared with surgical excision for low-risk nodular basal cell carcinoma. Br J Dermatol 2007;157:401–403.
  10. Itoh Y, Henta T, Ninomiya Y, Tajima S, Ishibashi A: Repeated 5-aminolevulinic acid-based photodynamic therapy following electro-curettage for pigmented basal cell carcinoma. J Dermatol 2000;27:10–15.
  11. Soler AM, Warloe T, Berner A, Giercksky KE: A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage. Br J Dermatol 2001;145:467–471.
  12. Soler AM, Warloe T, Tausjo J, Berner A: Photodynamic therapy by topical aminolevulinic acid, dimethylsulphoxide and curettage in nodular basal cell carcinoma: a one-year follow-up study. Acta Derm Venereol 1999;79:204–206.
  13. Ziolkowski P, Osiecka BJ, Siewinski M, Bronowicz A, Ziolkowska J, Gerber-Leszczyszyn H: Pretreatment of plantar warts with azone enhances the effect of 5-aminolevulinic acid photodynamic therapy. J Environ Pathol Toxicol Oncol 2006;25:403–409.
  14. De Rosa FS, Marchetti JM, Thomazini JA, Tedesco AC, Bentley MV: A vehicle for photodynamic therapy of skin cancer: influence of dimethylsulphoxide on 5-aminolevulinic acid in vitro cutaneous permeation and in vivo protoporphyrin IX accumulation determined by confocal microscopy. J Control Release 2000;65:359–366.
  15. Ziolkowski P, Osiecka BJ, Oremek G, et al: Enhancement of photodynamic therapy by use of aminolevulinic acid/glycolic acid drug mixture. J Exp Ther Oncol 2004;4:121–129.
  16. Pierre MB, Ricci E Jr, Tedesco AC, Bentley MV: Oleic acid as optimizer of the skin delivery of 5-aminolevulinic acid in photodynamic therapy. Pharm Res 2006;23:360–366.
  17. Bodde HE, Roemele PE, Star WM: Quantification of topically delivered 5-aminolevulinic acid by lontophoresis across ex vivo human stratum corneum. Photochem Photobiol 2002;75:418–423.
  18. Gelfuso GM, Figueiredo FV, Gratieri T, Lopez RF: The effects of pH and ionic strength on topical delivery of a negatively charged porphyrin (TPPS4). J Pharm Sci 2008;97: 4249–4257.
  19. Rhodes LE, Tsoukas MM, Anderson RR, Kollias N: Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin. J Invest Dermatol 1997;108:87–91.
  20. Ramstad S, Le Anh-Vu N, Johnsson A: The temperature dependence of porphyrin production in Propionibacterium acnes after incubation with 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA). Photochem Photobiol Sci 2006;5:66–72.
  21. van den Akker JT, Boot K, Vernon DI, et al: Effect of elevating the skin temperature during topical ALA application on in vitro ALA penetration through mouse skin and in vivo PpIX production in human skin. Photochem Photobiol Sci 2004;3:263–267.
  22. Liu HF, Xu SZ, Zhang CR: Influence of CaNa2 EDTA on topical 5-aminolaevulinic acid photodynamic therapy. Chin Med J (Engl) 2004;117:922–926.
  23. Berg K, Anholt H, Bech O, Moan J: The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells. Br J Cancer 1996;74:688–697.
  24. 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 1995;28:213–218.
  25. Fang JY, Lee WR, Shen SC, Fang YP, Hu CH: Enhancement of topical 5-aminolaevulinic acid delivery by erbium: YAG laser and microdermabrasion: a comparison with iontophoresis and electroporation. Br J Dermatol 2004;151:132–140.
  26. Lopez RF, Bentley MV, Begona Delgado-Charro M, Guy RH: Optimization of aminolevulinic acid delivery by iontophoresis. J Control Release 2003;88:65–70.
  27. Juzeniene A, Juzenas P, Kaalhus O, Iani V, Moan J: Temperature effect on accumulation of protoporphyrin IX after topical application of 5-aminolevulinic acid and its methylester and hexylester derivatives in normal mouse skin. Photochem Photobiol 2002;76:452–456.
  28. Juzeniene A, Juzenas P, Bronshtein I, Vorobey A, Moan J: The influence of temperature on photodynamic cell killing in vitro with 5-aminolevulinic acid. J Photochem Photobiol B 2006;84:161–166.
  29. Donnelly RF, Morrow DI, McCarron PA, et al: Microneedle-mediated intradermal delivery of 5-aminolevulinic acid: potential for enhanced topical photodynamic therapy. J Control Release 2008;129:154–162.
  30. Ma L, Moan J, Peng Q, Iani V: Production of protoporphyrin IX induced by 5-aminolevulinic acid in transplanted human colon adenocarcinoma of nude mice can be increased by ultrasound. Int J Cancer 1998;78:464–469.
  31. Uehlinger P, Ballini JP, van den BH, Wagnieres G: On the role of iron and one of its chelating agents in the production of protoporphyrin IX generated by 5-aminolevulinic acid and its hexyl ester derivative tested on an epidermal equivalent of human skin. Photochem Photobiol 2006;82:1069–1076.
  32. Choudry K, Brooke RC, Farrar W, Rhodes LE: The effect of an iron chelating agent on protoporphyrin IX levels and phototoxicity in topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol 2003;149:124–130.
  33. Curnow A, Pye A: Biochemical manipulation via iron chelation to enhance porphyrin production from porphyrin precursors. J Environ Pathol Toxicol Oncol 2007;26:89–103.
  34. Curnow A, MacRobert AJ, Bown SG: Comparing and combining light dose fractionation and iron chelation to enhance experimental photodynamic therapy with amino- levulinic acid. Lasers Surg Med 2006;38:325–331.
  35. Pye A, Campbell S, Curnow A: Enhancement of methyl-aminolevulinate photodynamic therapy by iron chelation with CP94:an in vitro investigation and clinical dose-escalating safety study for the treatment of nodular basal cell carcinoma. J Cancer Res Clin Oncol 2008;134:841–849.
  36. Campbell SM, Morton CA, 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.
  37. Moseley H, Brancaleon L, Lesar AE, Ferguson J, Ibbotson SH: Does surface preparation alter ALA uptake in superficial non-melanoma skin cancer in vivo? Photodermatol Photoimmunol Photomed 2008;24:72–75.
  38. Soler AM, Angell-Petersen E, Warloe T, et al: Photodynamic therapy of superficial basal cell carcinoma with 5-aminolevulinic acid with dimethylsulfoxide and ethylendiaminetetraacetic acid: a comparison of two light sources. Photochem Photobiol 2000;71:724–729.

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