**3. Photosensitizers**

The term *field cancerisation* or *field effect* is frequently used to describe extensive UV damage with recurrent, multiple AK, and the presence of a tissue with genetically altered cells is a risk

Our group has extensive experience in clinical PDT in various areas of medicine as in gyne‐ cology [4], infectious disease [5], and in particular in dermatology [6-7], and in this chapter will be discussed the advantagens and indications of the PDT for non-melanoma skin cancer

Photosensitized oxidations have been of interest to chemists and biologists since Raab's discovery that microorganisms are killed by light in the presence of oxygen and sensitizing

The mechanism of action of photosensitizers is divide in two different types and generally involves direct oxidation by hydrogen peroxide (H2O2), superoxide anion radical (O2 ∙) and hydroxyl radical (∙OH) (Type I reaction) of biological targets (membranes, proteins, and

The generation of Reactive Oxygen Species (ROS), in both types I or II, are dependent on the uptake of a photosensitizing dye, often a haematoporphyrin derivative, by the tumor or other abnormal target tissue, the subsequent irradiation of the tumor with visible light of an appropriate wavelength, and the presence of molecular oxygen [10]. An adequate concentra‐ tion of molecular oxygen is also needed for tissue damage. If any one of these components is absent, there is no photodynamic response, and the overall effectiveness therefore requires

PDT response is induced by more than one cellular mechanism. A photosensitiser can directly target the tumor cells, inducing necrosis or apoptosis (Figure 1) [11]. Alternatively, tumor

**Figure 1.** Treatment procedure for topical PDT. A) Skin cancer lesion; B) Cream application (MAL or ALA); C) Occlusion

energy transfer from triplet states to molecular oxygen (Type II reaction) [8-10].

careful planning of both tissue photosensitization and light dosimetry.

O2) that is mainly formed through

DNA), as well as oxidation mediated by singlet oxygen (1

necrosis can be induced by damaging its vasculature [12].

of the lesion; D) Illumination; E) Inflammation and tecidual necrosis; F) Curative

factor for cancer development, representing an indication for topical PDT [3].

and others conditions.

234 Highlights in Skin Cancer

**2. Basic principles**

dyes [1].

The photosensitizers are by definition any substance capable of making an organism, a cell or a substance photosensitive, with the photo-excitation of several types of molecules through energy transfer processes. Porphyrins, chlorines, phthalocyanines are the three main groups of studied photosensitizers (PSs). Porphyrins are the most frequently used PSs, but its systemic administration shows an important adverse factor in Dermatology. Due to the high accumu‐ lation and slow drug clearance from the skin, porphyrins lead to prolonged photosensitization of the organism after application [13]. The commercially available compounds promote a patient photosensitization that lasts for 4-6 weeks. These PDT patients must avoid sun exposure during this period, otherwise skin burns can be induced. This is the major drawback for indication of PDT in Dermatology.

The development of an ideal PDT sensitizer is still a major challenge since several character‐ istics must be contemplated. Main characteristics are: a) photo-excitation with red-infrared light; b) low dark toxicity; c) high stability; d) rapid clearance from the body; e) high affinity to abnormal cells (selectivity), and f) high rate of ROS production.

The main reactions observed with biological molecules are lipid peroxidation (cholesterol), cycloaddition (2 +2)-protein (reaction with tryptophan) and Diels-Alder reactions upon molecules in the genetic code (guanine). Porphyrin derivatives are indeed intersting molecules. Compounds such as porphyrins and chlorins, have the characteristics suitable for use in PDT due to the high molar extinction coefficients, high absorptivities in the region of the "thera‐ peutic window" (600-800 nm) and with high quantum yields of singlet oxygen production.

PDT can also be performed with topical use of 5-aminolevulinic acid (5-ALA) or by its ester methyl-aminolevulinate (MAL), which are both precursors in the biosynthesis of protopor‐ phyrin IX (PpIX), a native photosensitizing compound that accumulates in the cells. Proto‐ porphyrin IX (PpIX) has absorption peaks at 505, 540, 580 and 630 nm.

These compounds must be stored in the form of hydrochloride (R-NH3Cl), since in its neutral form rapidly suffers degradation. Studies including a few with 5-year follow-up, have shown that ALA and MAL-PDT are comparable to other modalities in the treatment of superficial lesions considering their efficacy and with equivalent or superior cosmetic outcomes [14-15]. ALA and MAL are not photosensitizers, they are precursors of endogenous PpIX (Figure 2).

**Figure 2.** Molecular structures of the PpIX precursors.

The fundamental difference between ALA and its methyl ester (MAL) is the more hydrophobic character of the MAL. Thus, MAL can better penetrate through the cell membranes and more easily reaches the deepest epidermal layers. However, the biosynthesis of protoporphyrin IX production from MAL is slightly more time consuming because of the need of hydrolysis of this compound.

D=I.t (1)

Photodynamic Therapy for Non-Melanoma Skin Cancer

. The PDT illumination

http://dx.doi.org/10.5772/55242

237

Energy doses delivered for the treatment of basal cell carcinoma and other dermal conditions

of a BCC lesion of 2 cm of diameter, for example, may be of 8 to 20 minutes, depending on the

Nonmelanoma skin cancer is the most frequent one in the world population. Currently, therapeutic options are surgical ressection, electrocoagulation, curettage, cryotherapy, immunomodulating agents, cytotoxic agents, chemotherapy, PDT, among others. PDT is a noninvasive technique with excellent cosmetic outcome, well tolerated by patients and with good healing results, when used for the initial stages of cancer lesions. Different studies show the technique effectiveness for BCC (Figure 3 and 4), presenting curative rates ranging from

**Figure 3.** Nodular BCC before (A) and 30 days after (B) PDT, treated with MAL 20% in 2 sessions and dose of 100J/cm2

**Figure 4.** Superficial BCC before (A) and 30 days after (B) PDT, treated with MAL 20% in 2 sessions and dose of

and with irradiances of 40-150 mW/cm2

are in the range of 40-150 J/cm2

chosen irradiation parameters.

**5. Clinical results**

52.2% to 100% [7, 23-28].

100J/cm2

Chlorin is a photosensitizer indicated in the cases of PDT using *i.v.* medication. It is derived from natural or synthetic tetrapyrroles, and an important feature is their strong light absorption in the spectralregionusuallyabove660nm.AsignificantadvantageofPDTusingchorinsisthereduced duration of cutaneous photosensitivity as compared with other photosensitizers [16].

Recently, eight new chlorins with amphiphilic properties were synthesized from PpIX. Biological studies of some of these new chlorins indicate the great potential of these com‐ pounds as photosensitizers in PDT [17].
