The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology — to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?
Light has been used as therapy for more than three thousand years1,2. Ancient Egyptian, Indian and Chinese civilizations used light to treat various diseases, including psoriasis, rickets, vitiligo and skin cancer3. At the end of the nineteenth century in Denmark, Niels Finsen further developed 'phototherapy' — or the use of light — to treat diseases. He found that red-light exposure prevents the formation and discharge of smallpox pustules and can be used to treat this disease4. He also used ultraviolet light from the sun to treat cutaneous tuberculosis. This was the beginning of the modern light therapy, and, in 1903, Finsen was awarded a Nobel Prize for his discoveries (see TIMELINE).
More than 100 years ago, researchers also observed that a combination of light and certain chemicals could induce cell death. In 1900, German medical student Oscar Raab reported that certain wavelengths were lethal to infusoria — including a species of Paramecium — in the presence of acridine5. In the same year, a neurologist in France named J. Prime found that epilepsy patients who were treated with oral EOSIN developed DERMATITIS in sun-exposed areas6. Later, Herman Von Tappeiner and A. Jesionek treated skin tumours with topically applied eosin and white light in 1903 (Ref. 7); they described this phenomenon as 'PHOTODYNAMIC ACTION'8.
Experiments to test combinations of reagents and light led to modern photodynamic therapy (PDT). PDT involves two individually non-toxic components that are combined to induce cellular and tissue effects in an oxygen-dependent manner (Fig. 1). The first component of PDT is PHOTOSENSITIZER — a photosensitive molecule that localizes to a target cell and/or tissue. The second component involves the administration of light of a specific wavelength that activates the sensitizer. The photosensitizer transfers energy from light to molecular oxygen, to generate reactive oxygen species (ROS). These reactions occur in the immediate locale of the light-absorbing photosensitizer. Therefore, the biological responses to the photosensitizer are activated only in the particular areas of tissue that have been exposed to light. Other photochemical reactions that do not use oxygen as an intermediate9 — for example, photoaddition to DNA — have also been developed. These reactions are called 'photochemotherapy'. One photochemotherapeutic, called 'psoralens', has been combined with ultraviolet A to treat psoriasis, vitiligo and to enhance immunotherapy10.
The most extensively studied photosensitizers so far are porphyrins, which were identified in the mid-nineteenth century. These compounds contain a porphin structure — four pyrrole rings connected by methine bridges in a cyclic configuration — along with a side chain that is usually metallic. For example, the combination of iron with a porphin structure forms haem. W. Hausmann performed the first studies with these reagents. He treated paramecium and red blood cells with haematoporphyrin and light, and reported that this combination killed the cells. In addition, he reported skin reactions in mice that were exposed to light after haematoporphyrin administration11. In 1913, the German scientist Friedrich Meyer–Betz was the first to treat humans with porphyrins, testing the effects of 200 mg of haematoporphyrin on his own skin12. He observed swelling and pain specifically in light-exposed areas.
In the 1960s, Richard Lipson and colleagues initiated the modern era of PDT at the Mayo Clinic13,14. These studies involved a compound that was developed by Samuel Schwartz called 'haematoporphyrin derivative' (HPD)15. To prepare this derivative, crude haematoporphyrin was treated with acetic and sulphuric acids, filtered and then neutralized with sodium acetate. The precipitate was then resolved in saline to produce HPD. Lipson and E.J. Baldes then showed that HPD localized to tumours, where it emitted fluorescence. Because this derivative could also be administered at much smaller doses than crude haematoporphyrin, it held promise as a diagnostic tool16. The mechanisms by which photosensitizers such as HPD selectively accumulate in tumours are complex and not fully understood. It is presumably because of the high vascular permeability of the agents, as well as their affinity for proliferating endothelium and the lack of lymphatic drainage in tumours17,18.
The therapeutic application of PDT to patients with cancer took a long time to develop since the first experiments of Von Tappeiner and Jesionek were carried out in 1903. In 1972, I. Diamond and colleagues postulated that the combination of the tumour-localizing and tumour-phototoxic properties of porphyrins might be exploited to kill cancer cells19. In vivo studies revealed that PDT delayed the growth of gliomas that were implanted in rats. Tumour growth was suppressed for 10–20 days, but eventually, viable areas from deeper regions of the tumours began growing again. A significant breakthrough occurred in 1975 when Thomas Dougherty and co-workers reported that administration of HPD and red light completely eradicated mammary tumour growth in mice20. In the same year, J.F. Kelly and co-workers reported that light activation of HPD also eliminated bladder carcinoma in mice21.
In 1976, Kelly and co-workers initiated the first human trials with HPD — in patients with bladder cancer22. Five patients were diagnosed with the cancer using HPD. It was also used to treat one patient with recurrent bladder carcinoma who had failed transurethral resections, radiotherapy and chemotherapy. In this patient, HPD slowed tumour growth, and tumour necrosis was seen in the areas that received PDT. In a second study by Dougherty et al., 25 patients with a total of 113 primary or secondary skin tumours were treated with HPD. A complete response was observed in 98 tumours, a partial response was observed in 13 tumours and 2 tumours were found to be treatment resistant23. Following the preliminary successes in treating bladder and skin tumours, Y. Hayata and colleagues used PDT to treat obstructing lung tumours24. Bronchoscopic analysis revealed tumour growth delay in most patients, but only one out of fourteen patients was cured.
In 1984, J.S. McCaughan and colleagues used PDT to treat patients with oesophageal cancer25, O.J. Balchum and colleagues used PDT to treat patients with lung cancer26 and, 1 year later, Y. Hayata and colleagues used PDT to treat patients with gastric carcinoma27. All of these studies showed promising responses in early-stage patients, so PDT was recommended for patients with early-stage cancers that were inoperable, due to other complications. Patients with breast cancer28,29,30, gynaecological tumours31,32,33, intraocular tumours34,35,36, brain tumours37,38,39,40, head and neck tumours41,42, colorectal cancer43,44, cutaneous malignancies45,46, intraperitoneal tumours47, mesothelioma48, cholangiocarcinoma49 and pancreatic cancer50 were subsequently treated with PDT. However, this technique has only shown limited success in further studies, due to issues surrounding specificity and potency of photosensitizers. Another confounding factor is that PDT has been tested largely in patients with advanced-stage diseases that are refractory to other treatments. In such cases, a local effect cannot usually significantly alter the outcome of a systemic disease18. More selective and potent sensitizers have been developed, and are now under investigation in clinical trials (Table 1). With this new line of drugs, as well as with better localization methods18 and improved protocols and equipment, the efficacy of PDT might be improved51.
Mechanism of action
One advantage of PDT is that the photosensitizer can be administered by various means, such as by intravenous injection or topical application to the skin. However, these affect its biodistribution. Because biodistribution changes over time, the timing of light exposure is another way to regulate the effects of PDT. Following the absorption of light (photons), the sensitizer is transformed from its ground state (singlet state) into a relatively long-lived electronically excited state (triplet state) via a short-lived excited singlet state52. The excited triplet can undergo two kinds of reactions (Fig. 2). First, it can react directly with a substrate, such as the cell membrane or a molecule, and transfer a hydrogen atom (electron) to form radicals. These radicals interact with oxygen to produce oxygenated products (type I reaction). Alternatively, the triplet can transfer its energy directly to oxygen, to form singlet oxygen — a highly ROS (type II reaction). Because the effects of almost all PDT drugs are oxygen dependent, photosensitization typically does not occur in anoxic areas of tissue. In vivo studies showed that induction of tissue hypoxia, by clamping, abolished the PDT effects of porphyrins53.
Both type I and type II reactions occur simultaneously, and the ratio between these processes depends on the type of sensitizer used, the concentrations of substrate and oxygen, as well as the binding affinity of the sensitizer for the substrate. Because of the high reactivity and short half-life of the ROS, only cells that are proximal to the area of the ROS production (areas of photosensitizer localization) are directly affected by PDT54. The half-life of singlet oxygen in biological systems is <0.04 μs, and, therefore, the radius of the action of singlet oxygen is <0.02 μm54. The extent of photodamage and cytotoxicity is multifactorial and depends on the type of sensitizer, its extracellular and intracellular localization, the total dose administered, the total LIGHT EXPOSURE DOSE, light FLUENCE RATE, oxygen availability, and the time between the administration of the drug and light exposure. All of these factors are interdependent.
PDT's effects on tumours
It is now known that there are three main mechanisms by which PDT mediates tumour destruction17,18. In the first case, the ROS that is generated by PDT can kill tumour cells directly. PDT also damages the tumour-associated vasculature, leading to tumour infarction. Finally, PDT can activate an immune response against tumour cells. These three mechanisms can also influence each other. The relative importance of each for the overall tumour response is yet to be defined. It is clear, however, that the combination of all these components is required for long-term tumour control.
Direct tumour-cell killing. In vivo exposure of tumours to PDT has been shown to reduce the number of clonogenic tumour cells, through direct photodamage55. However, complete tumour eradication is not always fully realized by this mechanism alone for many reasons. One reason is non-homogenous distribution of the photosensitizer within the tumour. Furthermore, in 1995, Mladen Korbelik and colleagues showed that both intravenously administered photosensitizer accumulation and the level of tumour-cell killing decrease with the distance of tumour cells from the vascular supply56.
Another parameter that can limit direct tumour-cell destruction is the availability of oxygen within the tissue that is targeted by PDT. Oxygen shortage can arise as a result of the photochemical consumption of oxygen during the photodynamic process, as well as from the immediate effects of PDT on the tissue microvasculature. Rapid and substantial reduction in the tissue oxygen tension during and after illumination of photo-sensitized tissue have been reported57,58. Depending on the localization of the photosensitizer at the time of illumination, oxygen tension can increase transiently59. Although the development of microvascular damage and hypoxia after PDT have been shown to contribute to the long-term tumour response, the reductions in oxygen that occur during PDT can limit the response. There are two ways to overcome this problem. One is to lower the light fluence rate to reduce oxygen consumption rate, and the other is to fractionate the PDT light delivery to allow re-oxygenization of the tissue60,61. The extent of modulation by fluence rate is dependent on the localization of the photosensitizer62.
Vascular damage. The viability of tumour cells also depends on the amount of nutrients supplied by the blood vessels. In turn, formation and maintenance of blood vessels depend on growth factors produced by tumour or host cells63,64. Targeting the tumour vasculature is therefore one promising approach to cancer treatment. In the past 15 years, there have been a number of reports of PDT causing microvascular collapse65,66,67,68, leading to severe tissue hypoxia and anoxia69,70,71. As early as 1989, Barbara Henderson and colleagues showed in a fibrosarcoma mouse model that Photofrin-based PDT (Photofrin is a photosensitizer produced by Axcan Pharma, Montreal, Canada) induced vascular shutdown, limiting the oxygen supply to the tumour72. Pre-clinical in vivo studies that were performed last year with the photosensitizer MV6401 — a pyropheophorbide derivative (Miravant Medical Technologies, Santa Barbara, California) — showed a biphasic vascular response following PDT. The first, immediate response was vasoconstriction. After three hours, a second, long-term response, characterized by thrombus formation, occurred68. This response could be inhibited with heparin. These vascular effects were associated with a delay in tumour growth. Previous studies with other photosensitizers, such as a benzoporphyrin derivative (BPD)67, HPD65 and Photofrin66 also reported vascular constriction, thrombus formation and inhibition of tumour growth. On the other hand, expression of vascular endothelial growth factor (VEGF) and cycloxygenase (COX)-2 — both potent angiogenic factors — were upregulated during PDT (Refs 73, 74; and D.E. Dolmans et al., unpublished observations). These effects were presumably due to the ROS formation and hypoxia that was induced by PDT. Further studies are required to determine the long-term effects of PDT on tumour vasculature.
Immune response. Studies in the late 1980s and early 1990s also reported infiltration of lymphocytes, leukocytes and macrophages into PDT-treated tissue, indicating activation of the immune response52,76. Differences in the nature and intensity of the inflammatory reaction between normal and cancerous tissues could contribute to the selectivity of PDT-induced tissue damage. The inflammatory process is mediated by factors such as vasoactive substances, components of the complement and clotting cascades, acute-phase proteins, proteinases, peroxidases, ROS, leukocyte chemoattractants, cytokines, growth factors and other immunoregulators. The inflammatory cytokines interleukin (IL-6) and IL-1, but not tumour necrosis factor-α (TNF-α), have been shown to be upregulated in response to PDT77. In 1996, Wil de Vree and colleagues also reported that PDT activated neutrophil accumulation, which slowed tumour growth78. Depletion of neutrophils in tumour-bearing mice decreased the PDT-mediated effect on tumour growth78.
In 1996, Mladen Korbelik and colleagues compared the long-term effects of PDT on tumour growth in normal Balb/C and immunodeficient mice. Whereas short-term tumour responses to Photofrin PDT were similar, long-term effects were quite different, as tumour recurrence occurred more frequently in the immunocompromised mice. This effect was reversed by bone-marrow transplants from immunocompetent Balb/C donors. These results indicate that, whereas the direct effects of PDT can destroy the bulk of the tumour, the immune response is required to eliminate the surviving cells79.
In 1999, Korbelik and colleagues reported that PDT generated tumour-sensitized immune cells that could be recovered from lymphoid sites distant to the treated tumour at different time intervals after PDT80. An interesting observation was also made by Barbara Henderson and colleagues, who reported that a tumour-cell lysate that was isolated following PDT with Photofrin could be used to vaccinate mice against the development of further tumours, indicating the induction of tumour-specific immunity81. This vaccination approach has been shown to be more effective at activating an immune response than lysates made from tumours that were exposed to ultraviolet or ionizing irradiation. These PDT vaccines seem to induce a cytotoxic T-cell response that involves induction of IL-12 expression. Studies with PDT and tumour-cell lysates indicate that PDT could have potential as a systemic immune therapy81. Further experiments are required to determine whether similar results can be obtained in patients who receive PDT.
Factors that affect PDT efficacy
Tumour localization of the photosensitizer is an important factor that determines PDT efficacy. Researchers therefore set out to improve the localization of the photosensitizer to specific regions of the tumour tissue (Box 1). In the past years, a number of more selective photosensitzers have been developed. For example, MV6401 has been shown to selectively localize to the tumour vasculature68. Drug localization is known to be determined by vascular permeability and interstitial diffusion, which depend on molecular size, configuration, charge, and hydrophilic or lipophilic property of the compound, as well as physiological properties of blood vessels82. Binding of the drug with various components of the tissue can also influence its transport and retention in tumours82,83.
The interval between the sensitizer administration and light exposure was also another key factor in determining PDT efficacy. When a short interval (15 minutes) was allowed between drug and light administration, the sensitizer predominantly accumulated in the vascular compartment. This resulted in vascular stasis and thrombus formation, followed by indirect tumour-cell killing. Conversely, a longer interval (4 hours) between intravenous drug injection and light administration resulted in MV6401 localization to the extravascular compartment of the tumour, due to relatively slow leakage from the vasculature and interstitial diffusion84 (Fig. 3). In the treatment of most cancers, the interval between drug and light administration is typically longer — in the order of 24–72 hours — in the cases of Photofrin85 or meta-tetrahydroxyphenylchlorin (mTHPC, or Foscan, Biolitec Pharma, Scotland, UK)86. So, different time intervals between photosensitizer and light administration destroy tumour cells by different mechanisms and have different consequences59.
In the past year, PDT protocols have therefore been modified to optimize targeting of both the vascular and tumour-cell compartments84. Administration of photosensitzers at multiple time intervals before light activation (fractionated drug-dose PDT), was found to be the most effective way to target both tumour blood vessels and tumour cells. Fractionated drug-dose PDT regimens were reported to result in a superior therapeutic effect, compared to single-dose regimens such as anti-vascular PDT or antitumour-cell PDT, and were able to induce long-term tumour growth control84. This is one more example that the most effective way to attack a tumour is through the targeting of several compartments.
Another way to direct the photosensitizer to a certain cell type or compartment is to use specific targeting carriers, such as conjugated antibodies directed to tumour-associated antigens or vascular antigens, such as the ED-B domain87. Since the mid-1990s, photosensitizers have been developed that can localize to the mitochondria, plasma membrane, lysosomes and nuclei88. The site of action within a cell also contributes to the efficacy of PDT89. In fact, the mitochondria have been proposed to be some of the most effective subcellular targets for photodamage17,51. These factors are important to consider when combining PDT with other treatment modalities, such as therapeutics that are designed to target different subcellular regions or cell functions90.
Clinical applications of PDT
PDT was first approved in 1993 in Canada, using the photosensitizer Photofrin for the prophylactic treatment of bladder cancer. This is the most commonly used photosensitizer in the clinic today. The development of Photofrin arose from an initial discovery in 1983 by Thomas Dougherty, who showed that crude haematoporhyrin contains a range of different porphyrins. When these were converted to HPD by acetylation, additional porphyrins were produced, such as protoporphyrin and hydroxyethylvinyldeuteroporphyrin91. The following year, he proposed that the active component of HPD was composed of two porphyrin units linked by an ether bond92, and he named this compound dihaematoporphyrin ether (DHE). Photofrin is partially purified HPD — a mixture of mono-, di- and oligomers that all contain the porphyrin moiety.
The development of Photofrin was a breakthrough in PDT research, and this photosensitizer holds the largest number of approvals for clinical use (Table 1). Subsequent approvals for PDT with Photofrin were obtained in the Netherlands and France for the treatment of advanced-stage lung cancer, in Germany for the treatment of early-stage lung cancer, in Japan for early-stage oesophageal, gastric and cervical cancer, as well as cervical dysplasias, and in the United States for advanced oesophageal cancer (Table 2).
Although Photofrin is the most commonly used photosensitizer, there are several limitations of this compound. First, it consists of about 60 compounds and therefore it is difficult to reproduce its composition. Although the compound has a useful absorption maximum of 630 nm, its molar absorption coefficient at this wavelength is low (1,170 M−1cm−1). Therefore, high concentrations of sensitizer and light must be delivered to the tumour. Furthermore, Photofrin is not very selective for tumour tissue. Orenstein and colleagues93 reported low tumour to normal tissue ratios of Photofrin uptake in C26 colon-carcinoma-bearing mice. Finally, Photofrin causes long-lasting cutaneous photosensitivity, as it is absorbed by the skin94. For this reason, patients who have been treated with Photofrin have to avoid sunlight for 4–6 weeks.
So, significant efforts have been invested in the development of new sensitizers. In particular, there was a need for new compounds that absorb light at longer wavelengths (to facilitate tissue penetration of the light), compounds with greater tumour specificity and compounds with less skin photosensitivity. To this end, many other sensitizers have recently been developed and have entered clinical trials. Foscan is another photosensitizer that is now approved for the treatment of head and neck cancer. This chlorin photosensitizer95 requires very low drug doses (as little as 0.1 mg/kg body weight) and light doses (as low as 10 J/cm2) for efficacy. However, significant complications have also been observed because of its high potency96. PDT with 5-aminolevulinic acid (5-ALA, or Levulan, DUSA Pharma, Toronto, Canada) and 5-ALA methylesther (Metvix, Photocure, Oslo, Norway) are approved for treating actinic keratosis and basal-cell carcinoma of the skin, by topical application followed by blue or red light exposures, respectively.
Other developments in PDT
As well as the photodynamic effect that occurs after light administration, these agents also produce fluorescence, which can be used to detect tumours (Fig. 3). Haematoporphyrins, porphyrins, HPD and ALA-derivatives are all being tested for use in tumour detection. The first successful studies on photodetection were carried out in 1955 by Rassmussan-Taxdal and colleagues, who treated cancer patients with haematoporphyrin hydrochloride and were able to identify tumour cells during histological examination97. In the early 1960s, Richard Lipson went on to use HPD to localize tumours in patients undergoing bronchoscopy or oesophagoscopy for suspected malignant diseases14,16. In patients with these disorders, Photofrin was administered intravenously and the fluorescence was monitored with an endoscope or bronchoscope. Squamous-cell carcinoma showed increased fluorescence and more-invasive tumours showed increased contrast98. In the mid-1990s, J.C. Kennedy and colleagues reported successful treatment of skin disorders with topically administered 5-ALA99. This relatively new approach of locally administered PDT has been applied in the treatment and detection of superficial lesions100,101. 5-ALA has also been used to guide the surgical resection of glioblastoma multiforme102. Photodetection might also be used to detect and treat pre/early-malignant lesions, such as dysplasia or carcinoma in situ within Barrett's oesophagus103,104. PDT can also be used to enhance the delivery of membrane-impermeable drugs to the cytosol of target cells by the technique called photochemical internalization105.
PDT in other diseases. Today, the most popular application of PDT is in the treatment of age-related macular degeneration and other eye diseases that are related to neo-vascularization106. In 1999, Verteporfin (Novartis Inc., Basel, Switzerland) was approved in Canada107. Later, approval was granted in many other countries, including in the United States in 2000. As well as the treatment and detection of cancer and pre-cancerous lesions, and the use of PDT in ophthalmology, this strategy has been applied in cardiovascular diseases, dermatology and rheumatology. Paolo Ortu and colleagues pioneered the development of PDT for the treatment of arteries with intimal hyperplasia108. Other ongoing studies include PDT after stent implantation109. In dermatology, PDT is used to treat diseases such as psoriasis and scleroderma110,111. In the rheumatology field, PDT is being tested to treat arthritis112. Finally, PDT is going back to its origins in microbiology and being used to target microorganisms113,114.
PDT has been around for the past 100 years and has been an experimental clinical modality for the past two decades. In America, Asia and Europe, several photosensitizers have been approved for clinical use. Overall, PDT has the potential of being a palliative therapy or a primary therapy, depending on the specific indications.
Researchers are now investigating the ability to improve the tumour specificity of photosensitizers by conjugating them to tumour-associated antibodies. This approach has been used successfully to treat cancer in preclinical models115, and also to treat angiogenesis-related diseases of the eye116. However, there are problems associated with the use of large molecules (monoclonal antibodies) in PDT. These include complicated synthesis, transport barriers82,83,117 and potential toxicity.
In the future, it is likely that PDT will continue to be used as a stand-alone modality or in combination with chemotherapy, surgery, radiotherapy or other new strategies, such as anti-angiogenic therapy73. Other ways to improve PDT include the development of new photosensitizers, as well as the optimization of PDT protocols such as fractionation of light118 or drugs84. Well-designed clinical trials that involve selectively localized photosensitizers and convenient light sources will also improve the prospects for the use of PDT in cancer and other diseases.
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We thank R. Anderson, T. Hasan and J. S. Hill for their critical and constructive comments, and A. C. Moor for her input on various sensitizers.
Inflammation of the skin.
The first photosensitizer used in photodynamic therapy by von Tappeiner.
- FLUENCE RATE
The radiant energy incident per second across a sectional area of irradiated spot (power per unit area of light given in watts per square meter, W/m2; 1 W = 1 J/s).
- LIGHT EXPOSURE DOSE
The total energy of exposed light across a sectional area of irradiated spot (energy per unit area of exposed light, in joules per square meter, J/m2). The energy content of light is proportional to the wavelength of absorption.
- PHOTODYNAMIC ACTION
The reaction of cells to a chemical reagent (or photosensitizer), light and oxygen.
A chemical that is required for photodynamic action. A photosensitizer transfers energy from the light to generate reactive oxygen species. Photofrin is the most widely used photosensitizer so far.
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Dolmans, D., Fukumura, D. & Jain, R. Photodynamic therapy for cancer. Nat Rev Cancer 3, 380–387 (2003). https://doi.org/10.1038/nrc1071
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