Photodynamic therapy (PDT) usually involves the injection or topical application of a photosensitizing compound, which gets accumulated in the desired target cells, which are then irradiated by the light of a specific wavelength.[1] Hermann von Tappeiner, a professor from Germany, first coined the term 'photodynamic reaction' in the early 1900. It was preceded by a demonstration of the toxic effect of cumulative acridine orange (photosensitizer) on paramecia by his student Oscar Raab. The toxicity of acridine orange on paramecia was dependent on both concentration of the dye and the intensity of illumination.
Photodynamic therapy basically requires three things i.e. a photosensitizer, a light source, and oxygen. It involves the application of a topical photosensitizing agent over a targeted area, followed by activation of the agent by light irradiation. It will lead to the formation of reactive oxygen intermediates in the presence of oxygen. These intermediates act on essential cellular components leading to apoptosis and necrosis due to irreversible oxidization. Photodynamic therapy was discovered almost a century back, but its clinical application is relatively new. It was only after the 1970s that the wider use of photodynamic therapy started, and many different newer indications of PDT were added. PDT is used for several pathologies in dermatology.
Although the current role of PDT in ophthalmology in today's era is quite limited, it has been in use for about the past 30 years. Choroidal neovascular membrane underneath the fovea was the first indication for which PDT was put into use in ophthalmology in the early 1990s. For PDT in ophthalmology, verteporfin is the most preferred agent owing to its lipophilic properties, short half-life (which lessens the chances of it causing skin sensitivity) and also because it has a favorable absorption spectrum.[2]
Photodynamic therapy involves the application of a topical photosensitizing agent over a target area, followed by activation of the agent by light irradiation. It leads to the formation of reactive oxygen intermediates in the presence of oxygen. These intermediates act on essential cellular components leading to apoptosis and necrosis due to irreversible oxidization.When being used for ophthalmic purposes, the abnormal endothelial cells in the proliferating blood vessels selectively accumulate verteporfin.
The photochemical reaction is then initiated by irradiating verteporfin by the light of wavelength 689 nm. The light of wavelength 689 nm is chosen as it reaches the pathological endothelial cells within the choroid even with overlying blood, fibrotic tissue, and melanin. The far-red light has good penetration.[2] This irradiation excites the molecules of verteporfin, and these excited molecules react with oxygen molecules, which leads to the formation of free radicals. It is these free radicals that cause damage and death of the pathological endothelial cells. The death and damage are caused by activating a clotting cascade and platelet aggregation, which culminates in microvascular occlusion.
Photodynamic therapy is not only used in dermatology but also in the fields of general oncology, cardiovascular, and ophthalmology. The various indications in dermatology include:[3][4][5][6][7][8]
Indications of photodynamic therapy in the field of ophthalmology include:
Currently, two topical photosensitizers are FDA approved for dermatology indications. These are aminolevulinic acid and methyl aminolevulinate, the methylated derivative of ALA.
ALA is an unstable molecule and has low lipid solubility. This restricts the penetration of ALA through skin or cell membranes. Hence there is a requirement of longer contact times with ALA and limitation of ALA use in superficial skin diseases. Novel preparations of ALA have been developed, which have increased penetration and better molecular stability.
MAL, on the other hand, is a more stable molecule with better lipid solubility and hence deeper penetration as compared to ALA.
Light sources: Protoporphyrin 9 can be activated by visible light in the 404 to 420 nm (Blue wavelength, Soret band) and 635 nm (red wavelength regions).
Longer wavelengths of light result in deeper penetration. Hence blue light is used in the treatment of thin actinic keratoses, and red light is required for the treatment of deeper and thicker lesions and to target deeper tissues like the sebaceous glands.
Light sources include xenon lamps, halogen lamps, lasers (PDL, LP, Argon, Diode), IPL, LED, and fluorescence diagnostic systems.[22][3][4] When being put into use for ophthalmic purposes, verteporfin is injected intravenously as an infusion lasting for about 10 minutes. It is advisable to wait for 5 minutes as it allows the molecules of verteporfin to accumulate in the diseased endothelial cells. After a waiting period of 5 minutes, the eye of the patient being treated is irradiated by PDT laser, which uses the light of wavelength 689 nm.[2] The standard protocol for full fluence PDT uses an irradiance of 600 mW/cm, a fluence of 50 J/cm, for a duration of 83 seconds.
After cleansing the skin with a cleansing lotion and alcohol swab, the lesions should be debrided superficially, if required.[5] For ophthalmic purposes, the lesion size needs to be mapped prior to PDT. Indocyanine green (ICG) angiography helps delineate the total size of the lesion. Pupils of the patient need to be dilated with tropicamide+phenylephrine eye drop prior to the procedure. Laser spot size is decided on the basis of the greatest linear dimension (GLD) of the lesion mapped on ICG. The laser spot size is generally kept as >500 um than the GLD of the lesion.[2]
If there is any bleeding, it should be halted prior to the application of the selected photosensitizer. The incubation time required varies as per the photosensitizer and the indication for which PDT is being used. ALA requires an incubation period of 30 mins to 18 hours with or without occlusion. For MAL-PDT, the incubation period is of 3 hours with occlusion. Physical protection against the light with aluminum foil is required to prevent any effect of natural light. After the incubation period, the topical agent is removed with either a dry gauze or saline solution. ALA-PDT employs various light sources. MAL-PDT uses a 635 nm red light. The patient is advised to use chemical and physical photoprotective measures after the procedure.[5]
Ophthalmic Procedure:
Verteporfin is injected intravenously as an infusion. The infusion is given for about 10 min. The dose used is 6 mg/m of the body surface area.[23] After injecting verteporfin, it is advised to wait for about 5 minutes as it allows the molecules of verteporfin to accumulate in the pathological endothelial cells. After the wait of 5 minutes is over, the eye to be treated is irradiated by PDT laser, which uses the light of wavelength 689 nm. The laser delivery system is mounted on a slit lamp, which is used to visualize the fundus. The size of the laser spot to be used is determined by the greatest linear dimension (GLD) of the lesion as elucidated on angiography. The size of the laser spot exceeds the size of the lesion by roughly 500 um. For a standard, full fluence PDT, the irradiance used is 600 mW/cm with a fluence of 50 J/cm for a duration of 83 seconds.[2]
To enhance the safety profile of PDT and reduce the chances of subretinal hemorrhage, reduced fluence PDT is used, which uses a laser fluence of 25 J/cm.
Reduced dose PDT is also used at times, which uses half the amount of standard dose, that is, 3 mg/m of the body surface area.
Literature is limited to decide upon the adequate parameters for different chorioretinal disorders.
Adverse effects and complications of photodynamic therapy include:[3][24]
Carcinogenicity: keratoacanthomas, basal cell carcinoma, invasive squamous cell carcinoma, melanomas have been reported post-treatment with PDT. But as yet, the role of PDT in causing tumor has not been clearly defined and requires further elucidation.
The reason the use of PDT has declined over the years in ophthalmology is because of its complications, the most common being deterioration in vision due to subretinal hemorrhage.[25] Photosensitivity reactions after the injection of verteporfin are quite common. Therefore patients are advised not to step out into the sunlight and completely cover the skin to avoid light exposure to the skin for 48 hours after injection.
During intravenous infusion, verteporfin can extravasate into the areolar tissue surrounding the blood vessels, and it can lead to skin necrosis if not addressed promptly. Backache following verteporfin infusion is a relatively rare complication.
Approved as a therapeutic modality for actinic keratosis and some non-melanoma skin cancers, photodynamic therapy provides for a non-invasive, relatively lesser painful therapeutic modality with the advantage of excellent cosmesis and preservation of normal tissue. Photodynamic therapy is increasingly being applied to non-oncological indications in dermatology. Recent advances have provided for improved delivery systems for the photosensitizers. Also, there is ongoing research in the development of newer photosensitizers.
After exposure to light of appropriate wavelength (470-700 nm), the photosensitizing agent undergoes biochemical changes leading to the generation of reactive oxygen species, which then results in selective cytotoxic damage.
The topically applied agents are prodrugs, which, over time, are converted into protoporphyrin 9, which acts as the photosensitizer.[22][26] Mainly localized in mitochondria, protoporphyrin accumulates in the cells of premalignant and malignant lesions owing to their rapid proliferation and reduced ferrochelatase activity. It also accumulates in other structures, including blood vessels, melanin, and sebaceous glands.[21] The activation of the photosensitizer by the light of appropriate wavelength results in a series of chemical reactions, finally culminating in the formation of free oxygen radicals. These free radicals result in cytotoxicity and also vascular damage. This, in turn, activates the inflammatory response and the host immune responses. All these factors induce damage in the targeted tissue.[3]
Protoporphyrin 9 generated from the photosensitizers is metabolized fully into heme within a period of 24 to 48 hours, and hence this largely reduces prolonged cutaneous phototoxicity.[22]
The advantage of topical photosensitizers is that there is a minimal risk of generalized photosensitivity.[24]The role of PDT in present-day ophthalmology is quite limited owing to its difficult availability and high cost. Alternative therapies like anti-VEGF injections and laser photocoagulation, which have a better safety profile, have made the need for PDT to be felt a little lesser.
As multiple variables regulate the selectivity in photodynamic therapy, the clinical response in an individual patient is difficult to anticipate. These variables include uptake of the photosensitizer into the target tissue, metabolism of the prodrug into active photosensitizer, penetration, and selectivity of the light source. Another variable affecting PDT is the temperature of the tissue, with the warming of the tissues being reported to result in better efficacy of PDT.[21][7]
The advent of newer drug delivery systems and newer photosensitizers has propelled the field of photodynamic therapy forward. A combination of photodynamic therapy with other treatment modality has come up as a promising approach for improving the efficacy and decreasing the adverse effects associated with photodynamic therapy. The improved clinical outcome has been reported with the use of immunomodulation therapy like imiquimod cream along with photodynamic therapy.[27] [Level 3]
A novel concept of ambulatory phototherapy has opened avenues for the delivery of photodynamic therapy with significantly less pain and more convenience to the patients as compared to the standard photodynamic therapy.[28][29] [Level 3]
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