Photodynamic therapy

Photodynamic therapy
Close up of surgeons' hands in an operating room with a beam of light traveling along fiber optics for photodynamic therapy. Its source is a laser beam which is split at two different stages to create the proper therapeutic wavelength. A patient is given a photosensitive drug that is absorbed by cancer cells. During the surgery, the light beam is positioned at the tumor site, which then activates the drug that kills the cancer cells, thus photodynamic therapy (PDT).
MeSH	D010778

Photodynamic therapy (PDT) is used clinically to treat a wide range of medical conditions, including wet age-related macular degeneration and malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic.

Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen. The wavelength of the light source needs to be appropriate for exciting the photosensitizer to produce reactive oxygen species. The combination of these three components leads to the chemical destruction of any tissues which have either selectively taken up the photosensitizer or have been locally exposed to light. In understanding the mechanism of PDT it is important to distinguish it from other light-based and laser therapies such as laser wound healing and rejuvenation which do not require a photosensitizer.

In order to achieve the selective destruction of the target area using PDT while leaving normal tissues untouched, either the photosensitizer can be applied locally to the target area or photosensitive targets can be locally excited with light. For instance, in the treatment of skin conditions, including acne, psoriasis, and also skin cancers, the photosensitizer can be applied topically and locally excited by a light source. In the local treatment of internal tissues and cancers, after photosensitizers have been administered intravenously, light can be delivered to the target area using endoscopes and fiber optic catheters (see figure).

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, PDT can be targeted to the blood carrying vasculature that supplies nutrients to tumours, increasing further the destruction of tumours.

Photosensitizers can also target many viral and microbial species, including HIV and MRSA. 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.

Over the last thirty years, PDT has seen considerable development in a wide range of medical applications. At the cutting edge of new PDT developments, many scientists worldwide are exploring ways of enhancing photosensitizer efficacy and targeting, while new research in Russia looks to use PDT to kill internal pathogens such as mycobacterium tuberculosis, and a significant development in Asia involves whole body Next Generation PDT (NGPDT) using a tumour-specific chlorophyll-based photosensitizer to treat a wide variety of solid cancers, including deep tissue and multisite cancers.

History

While the applicability and potential of PDT has been known for over a hundred years, the development of modern PDT has been a gradual one, involving scientific progress in the fields of photobiology and cancer biology, as well as the development of modern photonic devices, such as lasers and LEDs.

PDT in ancient medicine

The earliest recorded treatments that exploited a photosensitizer and a light source, in this case sunlight, for medical effect can be found in ancient Egyptian and Indian sources. Annals over 3000 years old report the use of topically applied vegetable and plant substances to produce photoreactions in skin and cause a repigmentation of depigimented skin lesions, as seen with vitilago and leukoderma.

The photosensitizing agents used in these ancient therapies have been characterised with modern science as belonging to the psoralen family of chemicals. Psoralens are still in use today in PDT regimes to treat a variety of skin conditions, including vitiligo, psoriasis, neurodermitis, eczema, cutaneous T-cell lymphoma and lichen ruber planus.

20th century development of PDT

The first detailed scientific evidence that agents, photosensitive synthetic dyes, in combination with a light source and oxygen could have potential therapeutic effect was made at the turn of the 20th century in the laboratory of von Tappeiner in Munich, Germany. Historically this was a time when Germany was leading the world in the industrial synthesis of dyes.

While studying the effects of acridine on paramecia cultures, Oscar Raab, a student of von Tappeiner observed a toxic effect. Fortuitously Raab also observed that light was dependent for the killing of paramecia cultures to take place. Subsequent work in the laboratory of von Tappeiner showed that oxygen was essential for the 'photodynamic action' – a term coined by von Tappeiner.

With the discovery of photodynamic effects, von Tappeiner and colleagues went on to perform the first PDT trial in patients with skin carcinoma using the photosensitizer, eosin, Out of 6 patients with a facial basal cell carcinoma, treated with a 1% eosin solution and a long-term exposure either to sunlight or to arc-lamp light, 4 patients showed total tumour resolution and a relapse-free period of 12 months.

It was only much later, when Thomas Dougherty and co-workers at Roswell Park Cancer Institute, Buffalo NY, clinically tested PDT again. In 1978, they published striking results in which they treated 113 cutaneous or subcutaneous malignant tumors and observed a total or partial resolution of 111 tumors. In this impressive research, Dougherty also pioneered the use of fibre optic cables to deliver laser light directly to the site of the tumour and regulate the light dose. Following this, Dougherty went on to become a highly visible advocate and educator of PDT, sharing his research with other clinics in the USA and overseas, In 1986 he formed the International Photodynamic Association.

The active photosensitizer used in the clinical PDT trial by Dougherty was an agent called Haematoporphyrin Derivative (HpD), which was first characterised in 1960 by Lipson. In his research, Lipson wanted to find a diagnostic agent suitable for the detection of tumours in patients. With the discovery of HpD, Lipson went onto pioneer the use of endoscopes and HpD fluorescence to detect tumours.

As its name suggests, 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 a significantly greater uptake and affinity for porphyrins compared to normal quiescent tissues. This important observation, which underlies the success of PDT to treat cancers, had been established by a number of scientific researchers prior to the discoveries made by Lipson. In 1924, Policard first revealed the diagnostic capabilities of hematoporphyrin fluorescence when he observed that ultraviolet radiation excited red fluorescence in the sarcomas of laboratory rats. Policard hypothesized at the time that the fluorescence was associated with endogenous hematoporphyrin accumulation. In 1948, Figge with co-workers showed on laboratory animals that porphyrins exhibit a preferential affinity to rapidly dividing cells, including malignant, embryonic, and regenerative cells, and because of this, they proposed that porphyrins should be used in the treatment of cancer. Subsequently many scientific authors have repeated the observation that cancerous cells naturally accumulate porphyrins and have characterised a number of mechanisms to explain it.

HpD, under the pharmaceutical 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 wider international attention and grew in their clinical use, and lead to the first PDT treatments to receive U.S. Food and Drug Administration approval.

Modern development of PDT

Of all the nations beginning to use PDT in the late 20th century, the Russians were the quickest to advance its use clinically and to make many developments. One early Russian development was a new photosensitizer called Photochem which, like HpD, was derived from haematoporphyrin in 1990 by Professor Alexander. F. Mironov and coworkers in Moscow. Photochem 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 that underwent PDT using Photochem, with 62 percent having a total tumor resolution. Of the remaining patients, a further 29 percent had a partial tumor resolution, where the tumour at least halved in size. In those patients that had been diagnosed early, 92 percent of the patients showed complete resolution of the tumour.

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

From 1994 to 2001, Russia launched clinical trials of even more promising photosensitizers which offered a number of advantages over haematoporphyrin-derived agents. Most notably, these new photosensitizers exhibited a higher photodynamic activity in the red region of light, making them more suitable to treat deep tumors. The photosensitizers also had a faster clearance time from normal tissues, making them more selective for tumour cells. At present, PDT is still being developed within Russia. Most notably, in the application of PDT as an antimicrobial treatment for drug resistant MRSA and TB infections.

In a retrospective analysis published by the Ministry of Health of Russia of data where PDT was employed in Moscow Medical Centers from 1992 to 2001 to treat malignant tumors, a beneficial effect was seen in 94.4 percent of the patients. Of these, 56.2 percent showed a total tumor resolution, and 38.2 percent showed a partial tumor resolution. This data came from 408 patients' case histories, with a wide variety of cancers, including skin, mammary gland, mucous membrane of the oral cavity, tongue, lower lip, larynx, lung, esophagus, stomach, urinary bladder, and rectum.

PDT has also seen considerably development in Asia. Since 1990, the Chinese have been developing specialist clinical expertise with PDT using their own domestically produced photosensitizers, derived from Haematoporphyrin, and light sources. PDT in China is especially notable for the technical skill of specialists in effecting resolution of difficult to reach tumours .

Overall the beneficial effect of PDT in China between 1990 to 2001, as reported in the literature, show the same high percentages of total and partial tumour resolution for a wide variety of cancers as seen by the Russians. In 2006 it was reported that China had over 1100 clinics using PDT and that this number was growing to meet the demands brought about the rapid growth in the incidence of cancer seen in Asia over the last two decades.

Mechanism of action

The basis of PDT is the interaction of light with photosensitive agents to produce an energy transfer and a local chemical effect. This is broadly similar to what is seen in photosynthesis, although in this case, many photosensitizers work together to harvest light energy to produce chemical reactions. Of the many photosensitizers that have been used in PDT, each has its own unique excitation properties. Usually, the photosensitizer is excited from a ground singlet state to an excited singlet state. It then undergoes intersystem crossing to a longer-lived excited triplet state.

One of the few chemical species present in tissue with a ground triplet state is molecular oxygen. When the photosensitizer and an oxygen molecule are in proximity, an energy transfer can take place that allows the photosensitizer to relax to its ground singlet state, and create an excited singlet state oxygen molecule. Singlet oxygen is a very aggressive chemical species and will very rapidly react with any nearby biomolecules. Ultimately, these destructive reactions will kill cells through apoptosis or necrosis. PDT can be considered a form of targeted singlet oxygen chemotherapy, where the targeting is achieved with the combination of the photosensitizer (functioning as a catalyst) and intense light.

A similar example is that cattle may become photosensitive if they graze on plants that contain photosensitizing toxins, such as marigold (Tagetes).

Advantages and Limitations

PDT is considered to be both minimally invasive and minimally toxic, these advantages alone make PDT an attractive alternative. Being a non-toxic therapy, PDT has become common in China because traditionally the country doesn't favour toxic therapies.

Compared to radiotherapy, chemotherapy and surgical operation for the treatment of cancers, PDT is in almost all cases a much cheaper alternative. Furthermore, post-operative recovery after PDT is typically hours or days rather than weeks.

Unlike chemotherapy for cancer the effect of PDT can be localised and specificity of treatment is achieved in three ways:

• First, light is delivered only to tissues that a physician wishes to treat. In the absence of light, there is no activation of the photosensitizer and no cell killing.
• Second, photosensitizers may be administered in ways that restrict their mobility.
• Finally, photosensitizers may be chosen which are selectively absorbed at a greater rate by targeted cells.

An important factor in the successful use of PDT is that light is needed to activate photosensitizers. This factor, more than any other, limited the development of PDT because most wavelengths of light can not penetrate through more than one third of an inch (1 cm) of tissue using standard laser technology and low powered LED technology. Thus, limiting application of PDT to the treatment of tumours on or under the skin, or on the lining of some internal organs. One way around this limitation is to use hollow needles to get the light into deeper tissues. Another way involves new high-powered LED technology to achieve much greater depth of light penetration. Also, the development of photosensitizers which are excited at 750–900 nm, wavelengths of light to which the body is relatively transparent (see Near-infrared window in biological tissue), can achieve a greater depth of light penetration of up to 5 inches.

Photosensitizers

A wide array of photosensitizers for PDT exist. They can be divided into porphyrins, chlorophylls and dyes. Some examples include aminolevulinic acid (ALA), Silicon Phthalocyanine Pc 4, m-tetrahydroxyphenylchlorin (mTHPC), and mono-L-aspartyl chlorin e6 (NPe6).

Several photosensitizers are commercially available for clinical use, such as Allumera, Photofrin, Visudyne, Levulan, Foscan, Metvix, Hexvix, Cysview, and Laserphyrin, with others in development, e.g. Antrin, Photochlor, Photosens, Photrex, Lumacan, Cevira, Visonac, BF-200 ALA. Amphinex. Also Azadipyrromethenes.

Although these photosensitizers can be used for wildly different treatments, they all aim to achieve certain characteristics:

• High absorption at long wavelengths
  • Tissue is much more transparent at longer wavelengths (~700–850 nm). Absorbing at longer wavelengths would allow the light to penetrate deeper, and allow the treatment of larger tumors.
• High singlet oxygen quantum yield
• Low photobleaching
• Natural fluorescence
  • Many optical dosimetry techniques, such as fluorescence spectroscopy, depend on the drug being naturally fluorescent
• High chemical stability
• Low dark toxicity
  • The photosensitizer should not be harmful to the target tissue until the treatment beam is applied.
• Preferential uptake in target tissue

The major difference between different types of photosensitizers is in 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 has been shown to localize in the nuclear envelope and do its damage there. In contrast, ALA has been found to localize in the mitochondria and Methylene Blue in the lysosomes.

Targeted PDT

Some photosensitisers naturally accumulate in the endothelial cells of vascular tissue allowing 'vascular targeted' PDT, but there is also research to target the photosensitiser to the tumour (usually by linking it to antibodies or antibody fragments). It is currently only in pre-clinical studies.

Example treatment of skin cancer

As an example, consider PDT as a treatment for basal cell carcinoma (BCC). BCC is the most common form of skin cancer in humans. Conventional treatment of BCC involves surgical excision, cryogenic treatment with liquid nitrogen, or localized chemotherapy with 5-fluorouracil or other agents. A PDT treatment would involve the following steps.

• A photosensitizer precursor (aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) or levulinic acid (LA)) is applied.
• A waiting period of a few hours is allowed to elapse, during which time
  • ALA will be taken up by cells, and
  • ALA will be converted by the cells to protoporphyrin IX, a photosensitizer (see Porphyrin).
• The physician shines a bright red light (from an array of light-emitting diodes or a diode laser) on the area to be treated. The light exposure lasts a few minutes to tens of minutes.
  • Protoporphyrin IX absorbs light, exciting it to an excited singlet state;
  • Intersystem crossing occurs, resulting in excited triplet protoporphyrin IX;
  • Energy is transferred from triplet protoporphyrin IX to triplet oxygen, resulting in singlet (ground state) protoporphyrin IX and excited singlet oxygen;
  • Singlet oxygen reacts with biomolecules, fatally damaging some cells in the treatment area.
• Within a few days, the exposed skin and carcinoma will scab over and flake away.
• In a few weeks, the treated area has healed, leaving healthy skin behind. For extensive malignancies, repeat treatments may be required. It is also common to experience pain from the area treated.
• After the treatment the patient will need to avoid excessive exposure to sunlight for a period of time.

Other research

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

PDT is currently in clinical trials to be used as a treatment for severe acne. Initial results show have shown for it to be effective as a treatment only for severe acne, though some question whether it is better than existing acne treatments. The treatment causes severe redness and moderate to severe pain and burning sensation. (see also: Levulan)

See also

• Photomedicine
• Sonodynamic therapy
• Blood irradiation therapy

External links

• International Photodynamic Association
• Photochemical and Photobiological Sciences
• Photodiagnosis and Phototherapy Journal
• Biophotonicsworld
• Next Generation PDT
• Killing Cancer Charity
• Photodynamic Therapy for Cancer