Photodynamic therapy

Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death (phototoxicity).

PDT is used in treating acne, wet age-related macular degeneration, psoriasis, and herpes. It is used to treat malignant cancers, including head and neck, lung, bladder and skin.

Advantages lessen the need for delicate surgery and lengthy recuperation and minimal formation of scar tissue and disfigurement. A side effect is the associated photosensitisation of skin tissue.

Reactive oxygen species

In air and tissue, molecular oxygen (O2) occurs in a triplet state, whereas almost all other molecules are in a singlet state. Reactions between triplet and singlet molecules are forbidden by quantum mechanics, making oxygen relatively non-reactive at physiological conditions. A photosensitizer is a chemical compound that can be promoted to an excited state upon absorption of light and undergo intersystem crossing (ISC) with oxygen to produce singlet oxygen. This species is highly cytotoxic, rapidly attacking any organic compounds it encounters. It is rapidly eliminated from cells, in an average of 3 μs.

Photochemical processes

When a photosensitiser is in its excited state (3Psen*) it can interact with molecular triplet oxygen (3O2) and produce radicals and reactive oxygen species (ROS), crucial to the Type II mechanism. These species include singlet oxygen (1O2), hydroxyl radicals (•OH) and superoxide (O2−) ions. They can interact with cellular components including unsaturated lipids, amino acid residues and nucleic acids. If sufficient oxidative damage ensues, this will result in target-cell death (only within the illuminated area).]]

Type-II processes

Type-II processes involve the direct interaction of the excited triplet state photosensitiser (3Psen*) with ground state molecular oxygen (3O2, 3Σg); a spin allowed transition—the excited state photosensitiser and ground state molecular oxygen are of the same spin state (T). Amphinex and Azadipyrromethenes.

The major difference between photosensitizers is the parts of the cell that they target. Unlike in radiation therapy, where damage is done by targeting cell DNA, most photosensitizers target other cell structures. For example, mTHPC localizes in the nuclear envelope. In contrast, ALA localizes in the mitochondria and methylene blue in the lysosomes.

Cyclic tetrapyrrolic chromophores

Cyclic tetrapyrrolic molecules are fluorophores and photosensitisers. Cyclic tetrapyrrolic derivatives have an inherent similarity to the naturally occurring porphyrins present in living matter.

Porphyrins

Porphyrins are a group of naturally occurring and intensely coloured compounds, whose name is drawn from the Greek word porphura, or purple. These molecules perform biologically important roles, including oxygen transport and photosynthesis and have applications in fields ranging from fluorescent imaging to medicine. Porphyrins are tetrapyrrolic molecules, with the heart of the skeleton a heterocyclic macrocycle, known as a porphine. The fundamental porphine frame consists of four pyrrolic sub-units linked on opposing sides (α-positions, numbered 1, 4, 6, 9, 11, 14, 16 and 19) through four methine (CH) bridges (5, 10, 15 and 20), known as the meso-carbon atoms/positions. The resulting conjugated planar macrocycle may be substituted at the meso- and/or β-positions (2, 3, 7, 8, 12, 13, 17 and 18): if the meso- and β-hydrogens are substituted with non-hydrogen atoms or groups, the resulting compounds are known as porphyrins.

Strong absorption with a high extinction coefficient in the red/near infrared region of the electromagnetic spectrum (600–850 nm)—allows deeper tissue penetration. (Tissue is much more transparent at longer wavelengths (~700–850 nm). Longer wavelengths allow the light to penetrate deeper

First generation

Porfimer sodium

Porfimer sodium is a drug used to treat some types of cancer. When absorbed by cancer cells and exposed to light, porfimer sodium becomes active and kills the cancer cells. It is a type of photodynamic therapy (PDT) agent and also called Photofrin.

PDT was first discovered more than a century ago in Germany, it was not until Thomas Dougherty's when PDT became more mainstream. Prior to Dr. Dougherty, researchers had ways of using light-sensitive compounds to treat disease. Dougherty successfully treated cancer with PDT in preclinical models in 1975. Three years later, he conducted the first controlled clinical study in humans. In 1994, the FDA approved PDT with the photosensitizer porfimer sodium for palliative treatment of advanced esophageal cancer, specifically the palliation of patients with completely obstructing esophageal cancer, or for patients with partially obstructing esophageal cancer. Porfimer Sodium is also FDA-approved for the treatment of types of lung cancer, more specifically for the treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated and also FDA approved in the US for high grade dysplasia in Barrett's Esophagus.

Disadvantages associated with first generation photosensitisers include skin sensitivity and absorption at 630 nm permitted some therapeutic use, but they markedly limited application to the wider field of disease. Second generation photosensitisers were key to the development of photodynamic therapy.

Functional groups

Altering the peripheral functionality of porphyrin-type chromophores can affect photodynamic activity. Using PDT, pathogens present in samples of blood and bone marrow can be decontaminated before the samples are used further for transfusions or transplants. PDT can also eradicate a wide variety of pathogens of the skin and of the oral cavities. Given the seriousness that drug resistant pathogens have now become, there is increasing research into PDT as a new antimicrobial therapy.

Applications

Acne

PDT is currently in clinical trials as a treatment for severe acne. Initial results have shown for it to be effective as a treatment only for severe acne. A systematic review conducted in 2016 found that PDT is a "safe and effective method of treatment" for acne. The treatment may cause severe redness and moderate to severe pain and burning sensation in some people. (see also: Levulan) One phase II trial, while it showed improvement, was not superior to blue/violet light alone.

Cancer

The FDA has approved photodynamic therapy to treat actinic keratosis, advanced cutaneous T-cell lymphoma, Barrett esophagus, basal cell skin cancer, esophageal (throat) cancer, non-small cell lung cancer, and squamous cell skin cancer (Stage 0). Photodynamic therapy is also used to relieve symptoms of some cancers, including esophageal cancer when it blocks the throat and non-small cell lung cancer when it blocks the airways.

When cells that have absorbed photosensitizers are exposed to a specific wavelength of light, the photosensitizer produces a form of oxygen, called an oxygen radical, that kills them. Photodynamic therapy (PDT) may also damage blood vessels in the tumor, which prevents it from receiving the blood it needs to keep growing. PDT may trigger the immune system to attack tumor cells, even in other areas of the body.

PDT is a minimally invasive treatment that is used to treat many conditions including acne, psoriasis, age related macular degeneration, and several cancers such as skin, lung, brain, mesothelioma, bladder, bile-duct, esophageal, and head and neck cancers.

Photoimmunotherapy

Photoimmunotherapy is an oncological treatment for various cancers that combines photodynamic therapy of tumor with immunotherapy treatment. Combining photodynamic therapy with immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment.

Vascular targeting

Some photosensitisers naturally accumulate in the endothelial cells of vascular tissue allowing 'vascular targeted' PDT.

Verteporfin was shown to target the neovasculature resulting from macular degeneration in the macula within the first thirty minutes after intravenous administration of the drug.

Compared to normal tissues, most types of cancers are especially active in both the uptake and accumulation of photosensitizers agents, which makes cancers especially vulnerable to PDT. Since photosensitizers can also have a high affinity for vascular endothelial cells.

Ophthalmology

As cited above, verteporfin was widely approved for the treatment of wet age-related macular degeneration beginning in 1999. The drug targets the neovasculature that is caused by the condition.

Antimicrobial effects

Photodynamic skin disinfection is effective at killing topical microbes, including drug-resistant bacteria, viruses, and fungi. Photodynamic disinfection remains effective after repeat treatments, with no evidence of resistance formation. The method can effectively treat polymicrobial antibiotic resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus biofilms in a maxillary sinus cavity model.

History

Modern era

In the late nineteenth century, Niels Ryberg Finsen successfully demonstrated phototherapy by employing heat-filtered light from a carbon-arc lamp (the "Finsen lamp") in the treatment of a tubercular condition of the skin known as lupus vulgaris, for which he won the 1903 Nobel Prize in Physiology or Medicine. Subsequent work in von Tappeiner's laboratory showed that oxygen was essential for the 'photodynamic action' – a term coined by von Tappeiner.

Von Tappeiner and colleagues performed the first PDT trial in patients with skin carcinoma using the photosensitizer, eosin. Of six patients with a facial basal cell carcinoma, treated with a 1% eosin solution and long-term exposure either to sunlight or arc-lamp light, four patients showed total tumour resolution and a relapse-free period of 12 months.

In 1924 Policard revealed the diagnostic capabilities of hematoporphyrin fluorescence when he observed that ultraviolet radiation excited red fluorescence in the sarcomas of laboratory rats. Policard hypothesized that the fluorescence was associated with endogenous hematoporphyrin accumulation.

In 1948 Figge and co-workers showed on laboratory animals that porphyrins exhibit a preferential affinity to rapidly dividing cells, including malignant, embryonic and regenerative cells. They proposed that porphyrins could be used to treat cancer.

Photosensitizer Haematoporphyrin Derivative (HpD), was first characterised in 1960 by Lipson. Lipson sought a diagnostic agent suitable for tumor detection. HpD allowed Lipson to pioneer the use of endoscopes and HpD fluorescence. HpD is a porphyrin species derived from haematoporphyrin, Porphyrins have long been considered as suitable agents for tumour photodiagnosis and tumour PDT because cancerous cells exhibit significantly greater uptake and affinity for porphyrins compared to normal tissues. This had been observed by other researchers prior to Lipson.

Thomas Dougherty and co-workers at Roswell Park Comprehensive Cancer Center in Buffalo, New York, clinically tested PDT in 1978. They treated 113 cutaneous or subcutaneous malignant tumors with HpD and observed total or partial resolution of 111 tumors. Dougherty helped expand clinical trials and formed the International Photodynamic Association, in 1986.

John Toth, product manager for Cooper Medical Devices Corp/Cooper Lasersonics, noticed the "photodynamic chemical effect" of the therapy and wrote the first white paper naming the therapy "Photodynamic Therapy" (PDT) with early clinical argon dye lasers circa 1981. The company set up 10 clinical sites in Japan where the term "radiation" had negative connotations.

HpD, under the brand name Photofrin, was the first PDT agent approved for clinical use in 1993 to treat a form of bladder cancer in Canada. Over the next decade, both PDT and the use of HpD received international attention and greater clinical acceptance and led to the first PDT treatments approved by U.S. Food and Drug Administration Japan and parts of Europe for use against certain cancers of the oesophagus and non-small cell lung cancer. Photofrin had the disadvantages of prolonged patient photosensitivity and a weak long-wavelength absorption (630 nm). This led to the development of second generation photosensitisers, including Verteporfin (a benzoporphyrin derivative, also known as Visudyne) and more recently, third generation targetable photosensitisers, such as antibody-directed photosensitisers. Verteporfin, a porphyrin derivative, is activated at 690 nm, a much longer wavelength than Photofrin. It has the property of preferential uptake by neovasculature. It has been widely tested for its use in treating skin cancers and received FDA approval in 2000 for the treatment of wet age related macular degeneration. As such it was the first medical treatment ever approved for this condition, which is a major cause of vision loss.

Russian scientists pioneered a photosensitizer called Photogem which, like HpD, was derived from haematoporphyrin in 1990 by Mironov and coworkers. Photogem was approved by the Ministry of Health of Russia and tested clinically from February 1992 to 1996. A pronounced therapeutic effect was observed in 91 percent of the 1500 patients. 62 percent had total tumor resolution. A further 29 percent had >50% tumor shrinkage. In early diagnosis patients 92 percent experienced complete resolution.

Russian scientists collaborated with NASA scientists who were looking at the use of LEDs as more suitable light sources, compared to lasers, for PDT applications.

Since 1990, the Chinese have been developing clinical expertise with PDT, using domestically produced photosensitizers, derived from Haematoporphyrin. China is notable for its expertise in resolving difficult-to-reach tumours.

Miscellany

PUVA therapy uses psoralen as photosensitiser and UVA ultraviolet as light source, but this form of therapy is usually classified as a separate form of therapy from photodynamic therapy.

To allow treatment of deeper tumours some researchers are using internal chemiluminescence to activate the photosensitiser.

References

External links

International Photodynamic Association
Photodynamic Therapy for Cancer from the NCI