Photodynamic Therapy

Photodynamic Therapy

A Liu - 2007 -

What is phototherapy?

Phototherapy is essentially the usage of light, usually in specific wavelengths, in the treatment of a varied multitude of conditions. This includes the ultraviolet and infrared wavelengths of light, and not only the visible spectrum.

Phototherapy has been used to treat various skin-related conditions such as acne, psoriasis and eczema. This is when particular wavelengths of light are used. For example, wavelengths of the visible violet light, (present in sunlight, in the range of 400-420nm) activates a porphyrin (porphyrins are deeply coloured natural dyes вЂ" known to exist in red-coloured leaves and in red blood cells. They generally have a deep purple, or dark colour) in Propionibacterium acnes which damages and ultimately kills the bacteria. Or for psoriasis and eczema, where a particular ultraviolet wavelength suppresses the immune system and reduces the inflammatory response. Monochromatic infrared light emitted at about 890nm has even been shown effective through limited clinical studies, to help restore sensation and reduce pain in patients with neuropathies, and to improve circulation of non-healing ulcers, thereby increasing overall healing rate. It is believed that the infrared light promotes the release of nitric oxide into the bloodstream, which then increases local circulation and improving blood flow.

In cases of neonatal jaundice, usage of light therapy has shown to be effective, as the light energy creates isomerisation of the bilirubin and consequently transformation into compounds that the newborn can excrete via urine and stools.

Light therapy is even widely known for its use in treating certain affective disorders, such as Seasonal and Non-Seasonal Affective Disorder (SAD and NSAD), as well as delayed sleep phase syndrome.

Although light therapy can be extremely useful for these conditions, concerns have been expressed over the safety of light therapy. Most notable is the damaging and/or carcinogenic effect of prolonged exposure to ultraviolet light. Thus the ultraviolet wavelengths of light are filtered, unless used by the treatment. Though, often, the benefits of the treatment far outweigh the risks of damage. This is akin to the treatment of cancer via radiotherapy, where radiation is used to treat cancer, however the radiation is itself a potential cause of cancer, and secondary malignancies are seen in a very small minority of patients, usually many years after the course of radiation treatment. However, this risk is greatly outweighed by the reduction in risk conferred by treating the primary cancer in the vast majority of cases.

In this paper, we will concentrate on a particular branch of phototherapy, with promising and exciting developments in the treatment of serious and malignant skin-related conditions.

What is photodynamic therapy (PDT)?

Photodynamic therapy is basically a two-step process in which the topical or systemic delivery of photosensitive drugs is followed by irradiation with light. Light photons are absorbed by the photosensitiser, which generate reactive species e.g. singlet oxygen (1O2) or the hydroxyl radical, which are cytotoxic. In this case, the subsequent oxidation of proteins, amino acids and lipids leads to cell necrosis and apoptosis. The key characteristic of these photosensitisers is that they are highly selective, in that they penetrate and accumulate in the tumour cells or in the endothelium of newly formed vessels while, in the most part, avoiding the surrounding healthy tissue. The different mechanisms of penetration through the cell membrane and the different patterns of localisation at the subcellular level determine the type of cellular effect that happens.

After a brief background on photodynamic therapy, this paper will look into the chemistry of the photosensitisers and the mechanisms by which they work, the resulting biochemical- and photoimmunology of the photodynamic reaction as well as an overview of the light sources used in PDT. In this paper I hope to place more emphasis on the dermatological uses of PDT, but of course, a general fundamental knowledge of PDT first is vital.

A Brief History of Photodynamic Therapy

The basic principle of photodynamic therapy is not new in dermatology, as topically applied eosin red and erythrosine exposed to normal sunlight were used in the treatment of conditions like skin tumours, psoriasis, lupus vulgaris, molluscum contagiosum, syphilis and pityriasis versicolor over a century ago(Sziemies et al., 2001). However, the lack of safe and effective sensitisers, as well as sufficiently powerful or safely filtered light sources meant that the technique was unsuitable for realistic widespread clinical use.

The photobiological properties of the haematoporphyrin (HP) derivative (and its other form -porfimer sodium) have been known, and investigated over the last 30 years or so. However, interest in PDT in dermatology was not raised until the 1990s with the advent of several more suitable photosensitisers, like 5-aminolaevulinic acid and methyl aminoevulinate (ALA and MAL). Then, several new compounds (like benzoporphyrins and phthalocyanines вЂ" dubbed вЂ?second-generation’ synthetic sensitisers) became available that were pure, highly efficient, selective and safe, with only a short period of generalised skin sensitivity. They are currently under clinical evaluation but have not yet been approved for clinical use.

As more and more experimental and clinical evidence becomes available, the usage and future development of photodynamic treatments can become far more effective. However, at the same time, it is crucial to understand the basic principles of the photochemistry and photobiology behind PDT, including explanations of the different photosensitisers used, and the light sources used to irradiate them, overviews on general photochemistry; and specific issues such as drug safety, actions of tissue selectivity and subcellular target sites. And, importantly, I will also consider and discuss the main clinical evidence so far in the field of photodynamic therapy.

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The Photosensitisers Explained

Topical sensitisers: ALA and MAL

ALA is not a photosensitiser in its own right but it is metabolised to a photosensitive compound, protoporphyrin IX (PpIX), through the intrinsic haem cellular pathway (see figure 1). ALA synthase (ALAS) forms an ALA molecule from a glycine and a