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INTRODUCTION
Photodynamic treatment (PDT) was first described more than a century ago, but due to lack of appropriate photosensitizers it was virtually forgotten for over 50 years. General photosensitization brought about by the systemic nature of the drugs that were available at the time prevented its general use. With the development of a range of new drugs, PDT is now readily available as a new therapeutic option in various fields of medicine, particularly dermatology.
DEFINITION OF PDT
PDT is defined as the selective destruction of malignant or fast-growing cells by light activation of a photosensitizing substance in the presence of oxygen. However, new research has now broadened its indications. Of the many modern photosensitizers, the most commonly used in dermatology are the prodrugs 5-aminolevulinic acid (ALA) and its methyl ester (Me-ALA).
Living cells are capable of heme biosynthesis. This is, however, quantitatively restricted by the activity of intracellular ALA synthase, which limits the endogenous synthesis of ALA and thus all further steps of the heme synthesis. Heme itself, by means of a negative feedback, inhibits ALA synthase.
There is little ALA synthase activity in the normal cell nucleus, which makes ALA from the aminoacid glycine and succinyl coenzyme A. Normally, ALA is transferred from the mitochondrion into the cytosol where it is synthesized to coproporphyrinogen via porphobilinogen and uroporphyrinogen. The coproporphyrine is again transferred into the mitochondrion and protoporphyrinogen is synthesized. This then undergoes molecular transformation to protoporphyrin IX (PpIX). This is the origin of heme, which is made by adding Fe ++ via ferrochelatase. Heme has a strong negative feedback on the mitochondrial ALA synthase. Since the amount of intracellular iron is limited, PpIX – the photosensitizer – accumulates, rendering the cell susceptible to light of the appropriate wavelength.
Adding exogenous ALA bypasses the limiting step of endogenous ALA synthesis and leads to a significant increase in the intracellular quantity of porphyrins ( Fig. 6.1 ). Since heme synthesis depends on the cell’s activity, malignant cells, which are highly active, take up relatively more exogenous ALA and produce more PpIX, rendering them more sensitive to light irradiation. Neither ALA nor Me-ALA – the substances currently approved for the treatment of superficial skin cancer – are by themselves active, but they are precursors of the light-sensitizing compound PpIX.
ALA selectivity for malignant cells is about 1.5 times that for normal ones, while that of Me-ALA is over 8 times. This allows shorter application times for Me-ALA cream compared to ALA cream. Furthermore, most non-malignant cells are virtually left intact. Absorption of ALA and Me-ALA through normal skin is minimal and there is no increase in light sensitivity. Thus, in contrast to injectable photosensitizers, the topical application of the precursor of a physiological porphyrin has nearly zero systemic risk and general photosensitivity does not develop.
The preferential uptake of the completely innocuous precursor and subsequent endogenous synthesis of protoporphyrin by the target cells is the major advantage of using ALA or Me-ALA, thereby restricting the phototoxic effect to the application site. Irradiation with light, which induces an active state in the photosensitizer, stimulates it to generate reactive oxygen species (ROS). These then kill those target cells that preferentially synthesized or took up the photosensitizer ( Table 6.1 ). ROS induces cellular damage, causing in turn cytotoxicity and immunomodulation, and finally apoptosis, necrosis and vessel occlusion ( Fig. 6.2 ). The damage resulting from PDT needs to overwhelm cellular repair mechanisms, a level that is reached at what is referred to as the minimum photodynamic dose. The role of heat during light irradiation is not yet entirely clear. The photosensitizer is activated by light, which elevates electrons to a higher energy level causing fluorescence. Upon return of the photosensitizer to its normal state, electrons are donated to the oxygen, turning it into reactive oxygen species. These in turn cause direct cellular damage with immunomodulation and cytotoxicity, leading to apoptosis, cell death and vascular effects ( Fig. 6.2 ).
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DRUGS USED FOR PHOTODYNAMIC TREATMENT IN DERMATOLOGY
In dermatology two prodrugs are used that are taken up by the cells and converted into the potent photosensitizer protoporphyrin IX: ALA and Me-ALA. Other drugs that are used in ophthalmology, urology, cancer treatment and internal medicine (for example systemic ALA, verteporphin, ethyl etiopurpurin and mesotetraphenylporphine sulfonate) do not play an important role in dermatology.
5-Aminolevulinic Acid
In the USA, the Food and Drug Administration (FDA) approved ALA as the first topical photosensitizing agent for the treatment of actinic keratoses. Because it is a small hydrophilic molecule, ALA is readily absorbed through abnormal keratin while normal keratin protects healthy surrounding skin. ALA is converted to PpIX, which, as described above, is a potent photosensitizer, and cannot be further converted to the non-photosensitizing heme because of limited supplies of iron. Application times of up to 4 hours confine PpIX production mainly to the target site. Longer application may lead to a larger reaction area. Since PpIX is readily degraded by the absorbed light – a process called photobleaching or photodecomposition – photosensitization typically resolves within 24 hours of application, but patients should be advised not to expose the treatment area to (sun)light immediately after treatment. The maximal light absorption peak is at 409 nm, but smaller peaks occur at 509, 544, 584 and 635 nm. The FDA approval is based on a 14- to 18-hour application period even though efficacy has been demonstrated with shorter incubation periods (1 hour), which is more convenient for both patients and physicians.
Recently, a low-concentration, liposome-encapsulated ALA cream has become available for use in light-induced skin rejuvenation. Measurements of skin fluorescence distribution patterns by fluorescent photography after topical application of low concentrations of ALA (0.5 and 1% preparations encapsulated in liposomes) were compared to those obtained after treatment with 20% ALA in moisturizing cream. These showed that skin fluorescence intensity with the low-concentration, liposome-encapsulated ALA reached saturation level after approximately 2 hours. The fluorescence decayed linearly within 15 minutes of the end of the application and was back to baseline within 8 hours. In contrast, the fluorescence of areas treated for more than 1 hour with the more concentrated ALA preparation in moisturizing cream was very uniform, with a linear relationship to incubation time (0–3 hours). The fluorescent intensity (15.2–57.9%) continued to increase after the end of the treatment application, eventually reaching a fluorescence of 1.6–9 times that at the end of the application, 8 hours afterwards. Thus, by changing the ALA vehicle from a moisturizing cream to liposome encapsulation, the ALA concentration can be lowered by a factor of 40 and still induce the same skin fluorescence. This also eliminates the need for occlusion, and the low post-treatment fluorescence suggests a significantly reduced risk of post-treatment phototoxicity.
Aminolevulinic Acid Methyl Ester
Me-ALA was approved by the FDA in 2004 for the treatment of actinic keratoses. Me-ALA is provided as a 160 mg/g cream to be applied under occlusion for 3 hours followed by red light activation (570–670 nm with a total dose of 75 J/cm 2 , or by red LED light at a light dose of 37.5 J/cm 2 ), after which complete photobleaching should have occurred. Me-ALA is more lipophilic and has better specificity for tumors and diseased skin than ALA. However, Me-ALA and ALA were recently suggested to exhibit similar levels of efficacy.
LIGHT SOURCES FOR PDT
Red light activation generates heat, which makes PDT for tumors almost unbearable without cold air cooling; local anesthesia is an alternative. Red LED light causes much less discomfort.
ALA and Me-ALA are converted to PpIX, the main absorption peak of which is in the blue light spectrum at 409 nm. The use of this wavelength is limited, however, by its maximal penetration of only 1.5–2 mm. In the USA, Blu-U® (DUSA Pharmaceuticals, Wilmington, MA) and Omnilux Blue™ (Photo Therapeautics Inc., Carlsbad, CA) are available as blue light sources. Red light (>600 nm) is absorbed much less and higher energy levels are necessary to get the same effect as blue light, but red light has the advantage that it penetrates approximately 8–10 mm. This deeper penetration can, however, be limited by melanin. Red LED light sources are widely used in Europe, while intense pulsed light (IPL) is used in both the USA and Europe, particularly for photorejuvenation.
A great number of indications have been investigated in the last 20 years ( Table 6.2 ), but not all have proven to be of value.
| Premalignant and malignant lesions | Actinic keratoses, Bowen’s disease (squamous cell carcinoma in situ), superficial basal cell carcinoma, other non-melanotic skin cancers * , cutaneous T cell lymphoma, extramammary Paget’s disease * |
| Inflammatory conditions | Acne vulgaris, psoriasis * |
| Infections | Dermatophytosis, onychomycosis, leishmaniasis, warts * , molluscum contagiosum |
| Benign conditions | Sebaceous hyperplasia, sebaceous nevus |
| Cosmetic indications | Photorejuvenation |
* We, personally, do not consider these diagnoses to be good indications for PDT
PHOTODYNAMIC DIAGNOSIS
PDT is also useful for diagnosis (photodynamic diagnosis, PDD) of malignant skin lesions and their precursors, since dysplastic cells, which selectively take up more ALA or Me-ALA than normal ones, exhibit a characteristic purple-red fluorescence upon irradiation with violet-blue light (Wood’s light), thus outlining the extent of superficial skin cancers and/or differentiating them from inflammatory lesions.
Blue light treatment of acne is most probably a kind of endogenous PDT as Propionibacterium acnes produces porphyrins that act as endogenous photosensitizers. Propionibacterium acnes -inhabited follicles also show the characteristic porphyrin fluorescence.
CONTRAINDICATIONS AND RESTRICTIONS
Contraindications are rare, and limited to some specific photodermatoses as well as allergies to ALA and Me-ALA. Pigmented lesions are not indicated for PDT, as melanin is a fluorescence quencher and may also inhibit light penetration ( Table 6.3 ).
