Mechanism of action of PDT in acne
Photodynamic Therapy involves the use of a photosensitiser, which is taken up by the epithelial cells, and it is converted to protoporphyrin IX (PpIX).
Photosensitisers are compounds that have a stable electronic configuration and at ground state energy is in a singlet state. However, through light exposure, the absorbed photons convert the compound into a higher energy state. For PDT, various different types of photosensitisers have been used. Among these porphyrins, porphyrin precursors, phthalocyanines, and chlorines are included. More specifically in dermatology the most frequently used photosensitisers are aminolevulinic acid (ALA) and methyl-aminolevulinic acid (MAL).
There are many factors associated with the effectiveness of a photosensitiser. The ideal photosensitiser:
- is minimally toxic
- is taken up faster by abnormal (target) tissue as compared to normal tissue,
- is rapidly eliminated from normal tissue,
- it is activated at wavelengths that penetrate the target tissue and
- is capable of producing large amounts of cytotoxic product.
The useful photosensitisers in PDT are taken up by both normal and rapidly dividing (malignant) cells, but are eliminated less rapidly from neoplastic cells. This difference in clearance rate may be due to the greater number and permeability of blood vessels, lysosomes, mitochondria, plasma membranes and nuclei of tumour cells. PDT kills tumour cells by
- direct destruction by singlet oxygen,
- damage to blood vessels, and
- activation of immune response.
The rate at which the photosensitiser is localised in the target tissue and then eliminated from the target tissue and the surrounding structures helps to determine the timing and dosing of the light exposure. The said pharmacokinetic properties are significantly dependent on the type of photosensitiser and its mode of delivery.
A photosensitiser is usually produced endogenously during applications on the skin, after the application of a photosensitising agent to the skin. For instance, ALA can act as a photosensitising agent. Though not photosensitive, ALA applied to the skin penetrates into underlying tissue where it is converted to protoporphyrin IX (PpIX), a photosensitive compound.
Porphyrin-based photosensitisers, especially porfimer sodium (Photofrin, QLT Phototherapeutics Inc, Vancouver, BC, Canada), have been used to treat cancers of the bladder, lung, oesophagus, stomach, skin and cervix by PDT. Porphyrins absorb maximally at the Soret band (360 – 400 nm) and have found smaller peaks between 500 and 635 nm. Cutaneous applications of porphyrins sensitizers are limited because clearance of porphyrins is slow, leading to cutaneous photosensitivity for 4 -6 weeks.
Light – Tissue Interactions
The effectiveness of a photosensitising agent depends partly on how deeply and how selectively the agent penetrates the skin. In PDT, a source that emits light at wavelengths within the absorption spectrum of the photosensitiser must be available.
Three basic events occur when light is exposed to the skin:
- the light is reflected from the surface of the skin,
- the light is scattered by the skin after penetrating it, and
- the light is absorbed by structures within the skin.
Reflected light can be used for diagnostic purposes; however, it does not have a direct clinical effect. Scattered light also has no clinical effect. Light absorbed by specific structures in the skin is the only light that can lead to a clinical effect. When light is absorbed it is converted into different types of energy, such as heat or acoustical waves, or as in PDT, the excitation of other atoms
The absorption of light and its effects on tissue are related to several factors:
- wavelengths of the light,
- energy or intensity of the light, and
- chromophores in the tissue.
It is not necessary to analyse in detail these factors, but there are some simple concepts that should be grasped in order to better understand PDT. For any therapeutic effect to occur the light must reach the targeted tissue, be absorbed by it and have enough energy to cause the desired response.
In general, the longer the wavelength, the deeper the light penetrates tissue. Light at 630 nm penetrates up to 5 mm while 700-800-nm light may reach up to 2 cm. However, it is important to note that once the light is absorbed, by the photosensitiser or any other chromophore, it will not penetrate any deeper. For example, green light with a wavelength of 532 nm can penetrate up to 1 mm into non-pigmented tissue, while the much longer 10 600-nm infrared light can only penetrate 20-30 μm into tissue due to its water absorption. It is important to choose a light for activation that not only has deep penetration so it can reach the target but also that has no other competing absorbers n the surrounding tissue.
Most light used in cutaneous PDT is in the visible or near infrared spectrum. The reason for this is that all available sensitizers have absorption spectra within these wavelengths. Absorption peaks for porphyrins are at 410 (maximum), 505, 540, 580, and 630 nm. The amount of photoactivation depends on the amount of absorbable light that reaches the photosensitiser in the target tissue. The advantage of longer wavelengths is limited by how strongly he photosensitiser absorbs light at these long wavelengths. For example, 630-nm light penetrates more deeply into tissue than 410-nm than at 635 nm. This decreased absorption can be partially overcome by extending the time of light exposure or increasing the amount of light energy. Thus, the appropriate wavelength and dosage of light delivered depends on the depth of the target tumour as well as how well it is absorbed by the photosensitiser.
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