1.1.

Principle of PDT

PDT is based on the photodynamic reaction: use of a light-sensitive substance (a photosensitizer), combined with light of a visible wavelength, to destroy target cells. This toxic biochemical reaction is oxygen-mediated. The photosensitizer absorbs a photon of visible light and then transfers most of the absorbed energy to a molecule of oxygen (Fig. 1). This converts it into a relatively strong oxidizing agent known as singlet oxygen. As a consequence, in the tissues that have accumulated the sensitizer, light-induced singlet oxygen exerts a cytotoxic effect by causing lethal oxidative damage to biologically important structures.

Fig. 1

Mechanism of the photodynamic reaction: the photosensitizer ($S$) is activated by the visible light. Most absorbed energy is transferred to a molecule of oxygen, which in turn is transformed into highly reactive and cytotoxic singlet oxygen (${}^1{\text{O}}_2$). The oxidative damage is limited to the tissues rich in $S$.

The selection of a proper photosensitizer has posed the greatest challenge in the years of PDT development. A substance that is naturally occurring offers a sufficient balance between selective tissue accumulation and relatively short clearance of the body, namely the protoporphyrin IX (PpIX). PpIX is a natural photosensitizer that can be made by the human body and is an intermediate product in the biosynthesis of heme (Fig. 2). It accumulates in rapidly proliferating cells of premalignant and malignant lesions, as well as in other structures, such as blood vessels, melanin, and sebaceous glands. In addition, malignant cells exert reduced ferrochetalase activity, resulting in excessive accumulation of intracellular PpIX.²

Fig. 2

Biosynthesis pathway of heme.

In PDT, aminolevulinic acid (ALA) or its methylated derivative—methyl-aminolevulinate (MAL)—is applied to the skin for varying periods of time, thus bypassing the rate-limiting step in the biosynthesis of heme. This leads to the conversion of ALA/MAL to PpIX. The activation of the sensitizer is accomplished by light with a specific wavelength that corresponds to the maximum absorption spectra of the sensitizer. In an ideal situation, the consecutive tissue damage is selective and only the rapidly proliferating tissue with accumulated PpIX will be destroyed with any surrounding tissue damage.

4.1.

Sensitizer

Although the substances (ALA and MAL) used for local PDT in dermatology are generally referred to as photosensitizers, they are prodrugs. Once delivered to the viable epidermis, ALA/MAL is converted to PpIX, which is the endogenous photactivating agent. Within the next 24 to 48 h, PpIX is transformed to the photodynamically inactive heme.¹⁰

$\delta$-5-ALA is a low molecular weight, hydrophilic molecule that can penetrate the stratum corneum and then can be included in the biosynthesis pathway of heme [Fig. 3(a)]. In the United States, ALA is marketed as 20% topical solution of hydrochloride salt. A variety of custom-made preparations as emulsions and gels are available in practice.

Fig. 3

Chemical formula of aminolevulinic acid (a) and methylaminolevulinate (b).

In addition, further substances can enhance the accumulation of PpIX, such as desferrioxamine, and the adding of DMSO and EDTA to ALA can enhance the penetration of the precursor.¹¹

Esters of ALA are more commonly used in Europe. They are lipophilic derivates of ALA, which allows enhanced penetration through the lipid bilayers of the horny layer.¹² It has been shown that MAL [Fig. 3(b)] possesses better tumor selectivity and less patient discomfort compared to ALA.¹³ Sixteen percent MAL cream is registered in both the United States and Europe. During photodynamic diagnosis, MAL provided higher tumor contrast than ALA in basal cell carcinoma visualization.¹⁴ The authors concluded that MAL should be preferred for use in fluorescence diagnostics.

In recent years, new systems to carry sensitizers to the cells have been developed, such as nanostructural materials, polymeric and liposomal formulations of the sensitizers, and lipid nano-carrier-mediated nuclear targeting carriers.¹⁵

The list of substances applied in PDT is increasing and includes chlorins, bacteriochlorins, auxins, pheophorbides, purpurins, phthalocyanines, and naphthalocyanines.^16,17

4.2.

Light Source

Different light sources of coherent (lasers) or incoherent origin are applied in PDT. Coherence is lost within the first millimeters of penetration into the skin;¹⁸ therefore, the use of such light sources is not an obligatory prerequisite. Furthermore the use of lasers is more expensive and can be related to some difficulties during the exploitation.¹⁹ Incoherent light sources remain the golden standard for PDT, including a variety of broadband lamps, light-emitting diodes, and intense pulsed light systems. Table 2 summarizes the reports in the literature data about the light intensity and dosing in PDT with incoherent light sources. Beyond blue and red light, green and white light sources have also been occasionally reported in PDT.¹⁹

Table 2

Light dose and intensity for incoherent light sources for PDT.

Porphyrins exhibit peak absorption at approximately 405 nm (Soret band; blue light spectrum) as well as several $Q$ bands with absorption peaks in the red light spectrum. Red light exhibits deeper penetration profiles in the skin, therefore it is the only light approved for PDT of skin tumors.¹⁶

A recently developed protocol proposed the so-called daylight-mediated PDT for actinic keratoses.²⁰ In this setting, MAL is applied on the entire affected skin field and the patients are exposed to daylight with no further illumination with artificial light sources. A randomized multicenter study showed that this method is efficient even after a single treatment session.²⁰ A natural daylight exposure of an hour and a half was sufficient to gain efficacy. Thin lesions responded better than the moderate and thick actinic keratoses.