Photodynamic therapy
Encyclopedia
Photodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic. 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 laser
s and LED
s.
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 cancer
s, 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 targetted 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 targetting, 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.
.
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.
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.
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, esophugus, 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.
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).
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:
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.
s, chlorophyll
s and dye
s. 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 Azadipyrromethene
s.
Although these photosensitizers can be used for wildly different treatments, they all aim to achieve certain characteristics:
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.
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. Some photosensitizers in development are linked to antibodies
to target them at the tumour cells.
(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.
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
)
Photobiology
Photobiology is the scientific study of the interactions of light and living organisms. The field includes the study of photosynthesis, photomorphogenesis, visual processing, circadian rhythms, bioluminescence, and ultraviolet radiation effects...
and cancer biology, as well as the development of modern photonic devices, such as laser
Laser
A laser is a device that emits light through a process of optical amplification based on the stimulated emission of photons. The term "laser" originated as an acronym for Light Amplification by Stimulated Emission of Radiation...
s and LED
LEd
LEd is a TeX/LaTeX editing software working under Microsoft Windows. It is a freeware product....
s.
Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
. The wavelength of the light source needs to be appropriate for exciting the photosensitizer to produce reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
. 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
Light therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
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
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, and also skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
s, 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
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....
endothelial cells, PDT can be targetted to the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
carrying vasculature that supplies nutrients to tumours, increasing further the destruction of tumours.
Photosensitizers can also target many viral and microbial species, including HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and MRSA. Using PDT, pathogens present in samples of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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 targetting, while new research in Russia looks to use PDT to kill internal pathogens such as mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
, and a significant development in Asia involves whole body Next Generation PDT (NGPDT) using a tumour-specific chlorophyll
Chlorophyll
Chlorophyll is a green pigment found in almost all plants, algae, and cyanobacteria. Its name is derived from the Greek words χλωρος, chloros and φύλλον, phyllon . Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to obtain energy from light...
-based photosensitizer to treat a wide variety of solid cancers, including deep tissue and multisite cancers.
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 leukodermaLeukoderma
Leukoderma is a cutaneous condition, an acquired condition with localized loss of pigmentation of the skin that may occur after any number of inflammatory skin conditions, burns, intralesional steroid injections, postdermabrasion, etc....
.
The photosensitizing agents used in these ancient therapies have been characterised with modern science as belonging to the psoralen
Psoralen
Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...
family of chemicals. Psoralens are still in use today in PDT regimes to treat a variety of skin conditions, including vitiligo, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, neurodermitis, eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, 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
Acridine
Acridine, C13H9N, is an organic compound and a nitrogen heterocycle. Acridine is also used to describe compounds containing the C13N tricycle....
on paramecia
Paramecia
Paramecia is a non-mineralized Ediacaran alga with a differentiated, compartmentalized thallus; it probably had multiple phases in its lifecycle. Possible reproductive structures have been identified....
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
Eosin
Eosin is a fluorescent red dye resulting from the action of bromine on fluorescein. It can be used to stain cytoplasm, collagen and muscle fibers for examination under the microscope. Structures that stain readily with eosin are termed eosinophilic....
, 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
Roswell Park Cancer Institute
The Roswell Park Cancer Institute is a comprehensive cancer research and treatment center located in Buffalo, New York. Founded in 1898 by Dr. Roswell Park, it was the first dedicated medical facility for cancer treatment and research in the United States. The facility is involved in drug...
, 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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, esophugus, 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 excitationExcitation
-Science:* The excited state of an atom* The excitatory postsynaptic potential* The excitation provided with an electrical generator or alternator-Agitation:*Excitement...
properties. Usually, the photosensitizer is excited from a ground singlet
Singlet
A pair of spin-1/2 particles can be combined to form one of three states of total spin 1 called the triplet, or a state of spin 0 which is called the singlet. In theoretical physics, a singlet usually refers to a one-dimensional representation...
state to an excited singlet state. It then undergoes intersystem crossing
Intersystem crossing
Intersystem crossing is a radiationless process involving a transition between two electronic states with different spin multiplicity.-Singlet and triplet states:...
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
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
is a very aggressive chemical species and will very rapidly react with any nearby biomolecules. Ultimately, these destructive reactions will kill cells through apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
or necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
. PDT can be considered a form of targeted singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, 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
Phototoxin
Phototoxins are toxins that can cause allergic reactions in particularly susceptible individuals and which can cause dangerous photosensitivity in a much broader range of subjects.Phototoxins are common in:...
, such as marigold
Tagetes
Tagetes is a genus of 56 species of annual and perennial mostly herbaceous plants in the sunflower family . The genus is native to North and South America, but some species have become naturalized around the world. One species, T...
(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 it 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
Near-infrared window in biological tissue
The near-infrared window defines the range of wavelengths where light has its maximum depth of penetration in tissue. Within the NIR window, scattering is the most dominant light-tissue interaction, and therefore the propagating light becomes diffused rapidly...
, 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 porphyrinPorphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
s, chlorophyll
Chlorophyll
Chlorophyll is a green pigment found in almost all plants, algae, and cyanobacteria. Its name is derived from the Greek words χλωρος, chloros and φύλλον, phyllon . Chlorophyll is an extremely important biomolecule, critical in photosynthesis, which allows plants to obtain energy from light...
s and dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
s. Some examples include aminolevulinic acid (ALA), Silicon Phthalocyanine Pc 4, m-tetrahydroxyphenylchlorin (mTHPC), and mono-L-aspartyl chlorin
Chlorin
In organic chemistry, a chlorin is a large heterocyclic aromatic ring consisting, at the core, of three pyrroles and one pyrroline coupled through four methine linkages...
e6 (NPe6).
Several photosensitizers are commercially available for clinical use, such as Allumera, Photofrin, Visudyne, Levulan
Levulan
Levulan photodynamic therapy is a treatment method for certain skin conditions developed by DUSA Pharmaceuticals. The active ingredient is δ-aminolevulinic acid .-Actinic keratosis:U.S...
, Foscan, Metvix, Hexvix
Hexvix
Hexvix is an optical imaging agent developed by the Norwegian pharmaceutical company Photocure ASA. Hexvix is designed to enhance detection of bladder cancer, in particular carcinoma in situ , it reveals lesions that may not be seen with standard white light cystoscopy...
®, Cysview
Cysview
Cysview is an optical imaging agent designed to enhance detection of bladder cancer, in particular carcinoma in situ , it reveals lesions that may not be seen with standard white light cystoscopy. Cysview is marketed in Europe as Hexvix...
™, and Laserphyrin, with others in development, e.g. Antrin, Photochlor, Photosens
Photosens
Photosens is a mixture of sulfonated aluminium phtalocyanines with various degrees of sulfonation. Developed in Russia.It is a photosensitiser sometimes used in photodynamic therapy trials....
, Photrex, Lumacan, Cevira, Visonac, BF-200 ALA. Amphinex
Amphinex
Amphinex is a photosensitising agent used in photodynamic therapy for treating superficial cancers.It has had promising preliminary results in early trials on patients with advanced head and neck cancer...
. Also Azadipyrromethene
Azadipyrromethene
Azadipyrromethane is a dye and the name of a new class of experimental photosensitizers for photodynamic therapy.Some derivatives can usefully absorb in the near-infrared....
s.
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 photobleachingPhotobleachingPhotobleaching is the photochemical destruction of a fluorophore. In microscopy, photobleaching may complicate the observation of fluorescent molecules, since they will eventually be destroyed by the light exposure necessary to stimulate them into fluorescing...
- Natural fluorescenceFluorescenceFluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...
- Many optical dosimetry techniques, such as fluorescence spectroscopyFluorescence spectroscopyFluorescence spectroscopy aka fluorometry or spectrofluorometry, is a type of electromagnetic spectroscopy which analyzes fluorescence from a sample. It involves using a beam of light, usually ultraviolet light, that excites the electrons in molecules of certain compounds and causes them to emit...
, depend on the drug being naturally fluorescent
- Many optical dosimetry techniques, such as fluorescence spectroscopy
- 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
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
, 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
Methylene blue
Methylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
in the lysosomes.
Targeted PDT
Some photosensitisers naturally accumulate in the endothelial cells of vascular tissueVascular tissue
Vascular tissue is a complex conducting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue are the xylem and phloem. These two tissues transport fluid and nutrients internally. There are also two meristems associated with vascular tissue:...
allowing 'vascular targeted' PDT,
but there is also research to target the photosensitiser to the tumour (usually by linking it to antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
or antibody fragments). It is currently only in pre-clinical studies. Some photosensitizers in development are linked to antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
to target them at the tumour cells.
Example treatment of skin cancer
As an example, consider PDT as a treatment for basal cell carcinomaBasal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
(BCC). BCC is the most common form of skin cancer in humans. Conventional treatment of BCC involves surgical excision, cryogenic treatment with liquid nitrogen
Liquid nitrogen
Liquid nitrogen is nitrogen in a liquid state at a very low temperature. It is produced industrially by fractional distillation of liquid air. Liquid nitrogen is a colourless clear liquid with density of 0.807 g/mL at its boiling point and a dielectric constant of 1.4...
, or localized chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
with 5-fluorouracil or other agents. A PDT treatment would involve the following steps.
- A photosensitizer precursor (aminolevulinic acid (ALA) or methyl aminolevulinate (MAL)Methyl aminolevulinateMethyl aminolevulinate is a prodrug that is metabolised to Protoporphyrin IX used in photodynamic therapy. It is marketed as Metvix....
or levulinic acid (LA)Levulinic acidLevulinic acid, or 4-oxopentanoic acid, is an organic compound with the formula CH3CCH2CH2CO2H. It is a keto acid. This white crystalline is soluble in water, ethanol, and diethyl ether.-Synthesis and uses:...
) 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 IXProtoporphyrin IXProtoporphyrin IX, in the metabolism of porphyrin, is created by the enzyme protoporphyrinogen oxidase.-Heme b biosynthesis:In heme biosynthesis, the enzyme ferrochelatase converts it into heme b Protoporphyrin IX, in the metabolism of porphyrin, is created by the enzyme protoporphyrinogen...
, a photosensitizer (see PorphyrinPorphyrinPorphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
).
- The physician shines a bright red light (from an array of light-emitting diodeLight-emitting diodeA light-emitting diode is a semiconductor light source. LEDs are used as indicator lamps in many devices and are increasingly used for other lighting...
s 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
Levulan
Levulan photodynamic therapy is a treatment method for certain skin conditions developed by DUSA Pharmaceuticals. The active ingredient is δ-aminolevulinic acid .-Actinic keratosis:U.S...
)