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 would be given a photo sensitive drug (photofrin) containing cancer killing substances which are 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).

Photodynamic therapy (PDT), matured as a feasible medical technology in the 1980s at several institutions throughout the world, is used to eradicate premalignant and early-stage cancer and reduce the tumour size in end-stage cancers^[1] involving three key components: a photosensitizer, light (wavelength appropriate for the photosensitzer), and tissue oxygen. The light causes the photosensitizer to cause the oxygen to damage and kill the tissues exposed to the light.

It is an approved treatment for wet macular degeneration, and is also being investigated for treatment of psoriasis.

Treatment of internal organs may be achieved through the use of endoscopes and fiber optic catheters to deliver light, and intravenously-administered photosensitizers.

A great deal of research and clinical study is now underway to determine optimal combinations of photosensitizers, light sources, and treatment parameters for a wide variety of different cancers.

It is currently being tested as a treatment for severe acne.^[2][3][4]

History

The German physician Friedrich Meyer–Betz performed the first study with what was first called photoradiation therapy (PRT) with porphyrins in humans in 1913. Meyer–Betz tested the effects of haematoporphyrin-PRT on his own skin.^[5]

Thomas Dougherty of Roswell Park Cancer Center, among others worldwide, became a highly visible advocate and educator. Early patients were treated at Roswell, Los Angeles Children's Hospital, Los Angeles County Hospital, and other clinics and Hospitals in the USA and overseas.^[6]

It was John Toth, as product manager for Cooper Medical Devices Corp/Cooper Lasersonics, who acknowledged the "photodynamic chemical effect" of the therapy with early clinical argon dye lasers and wrote the first "white paper" renaming the therapy as "Photodynamic Therapy" (PDT). This was done to support efforts in setting up 10 clinical sites in Japan where the term "radiation" had negative connotations. PDT received even greater interest as result of Thomas Dougherty helping expand clinical trials and forming theInternational Photodynamic Association, in 1986.

Despite excellent results it is only slowly being adopted in the UK as compared to say Italy - in part due to lack of suitable equipment and training.

Mechanism of action

A photosensitizer is a chemical compound that can be excited by light of a specific wavelength. This excitation uses visible or near-infrared light. In photodynamic therapy, either a photosensitizer or the metabolic precursor of one is administered to the patient. The tissue to be treated is exposed to light suitable for exciting the photosensitizer. Usually, the photosensitizer is excited from a groundsinglet 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. (The specific targets depend heavily on the photosensitizer chosen.) Ultimately, these destructive reactions will kill cells through apoptosis or necrosis.

This mechanism is identical to the mechanism of the disease erythropoietic protoporphyria, which causes blistering in response to sun exposure due to a genetic defect in the same metabolic pathway.

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 a few 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.

Advantages and limitations

Unlike chemotherapy for cancer the effect of PDT can be localised. 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. ALA is taken up much more rapidly by metabolically active cells. Since malignant cells tend to be growing and dividing much more quickly than healthy cells, the ALA targets the unhealthy cells.

PDT can be much cheaper than the alternative radiotherapy or surgical operation and after care. Post operative recovery is typically hours or days rather than weeks.

A major limitation of PDT is that the light needed to activate most photosensitizers can not penetrate through more than one third of an inch (1 cm) of tissue using standard laser technology and low powered LED technology. Laser application of PDT is generally limited to the treatment of tumours on or under the skin, or on the lining of some internal organs. Moreover it is less effective in treatment of large tumours and metastasis for the same reason. However, new high-powered LED technology has been lab-tested to provide a depth of 2 inches from surface in a simulated breast tissue. Also, hollow needles have been used by some units to get the light into deeper tissues.^[7]

Photosensitizers

A wide array of photosensitizers for PDT exist. They can be divided into porphyrins, chlorophylls and dyes.^[8] Some examples includeaminolevulinic 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 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.^[8][9] Amphinex.^[10] Also Azadipyrromethenes.

Although these photosensitizers can be used for wildly different treatments, they all aim to achieve certain characteristics^[11]:

• 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,^[10] 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^[12]
• 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.^[13] In contrast, ALA has been found to localize in the mitochondria^[14] andMethylene Blue in the lysosomes.^[15]

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.^[16][17] Some photosensitizers in development are linked to antibodies to target them at the tumour cells.

Other research

To allow treatment of deeper tumours some researchers are using internal chemiluminescence to activate the photosensitiser.^[18]

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,^[19] 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

References

1. ^ http://www.clinuvel.com/skin-conditions/photodynamic-therapy-pdt-and-phototoxicity
2. ^ http://clinicaltrials.gov/ct2/show/NCT00706433?term=photodynamic+therapy+acne&rank=1
3. ^ Inglis, Leslie (June 23, 2005). "Acne sufferer finally sees the light; Early treatment can reduce scarring".
4. ^ "Laser therapy combo effectively clears acne, reduces oil production". The Times Of India.
5. ^ Meyer-Betz, Friedrich (1913). "Untersuchungen uber die Biologische (photodynamische) Wirkung des hamatoporphyrins und anderer Derivative des Blut-und Gallenfarbstoffs.". Dtsch. Arch. Klin. Med. 112: 476–503.
6. ^ Moan, J.; Q. Peng (2003). "An outline of the history of PDT". In Thierry Patrice. Photodynamic Therapy. Comprehensive Series in Photochemistry and Photobiology. 2. The Royal Society of Chemistry. pp. 1–18. doi:10.1039/9781847551658.
7. ^ "A Phase 3 Study of Talaporfin Sodium and Interstitial Light Emitting Diodes Treating Hepatocellular Carcinoma (HCC)".ClinicalTrials.gov. Retrieved October 4, 2008.
8. ^ ^a b Allison, Ron R; et al. (2004). "Photosensitizers in clinical PDT" (PDF). Photodiagnosis and Photodynamic Therapy (Elsevier) 1: 27–42. doi:10.1016/S1572-1000(04)00007-9.
9. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317568/ "A Review of Progress in Clinical Photodynamic Therapy" 2005
10. ^ ^a b O'Connor, Aisling E, Gallagher, William M, Byrne, Annette T (2009). "Porphyrin and Nonporphyrin Photosensitizers in Oncology: Preclinical and Clinical Advances in Photodynamic Therapy. Photochemistry and Photobiology, Sep/Oct 2009". Photochemistry and Photobiology.
11. ^ Wilson, Brian C; Michael S Patterson (2008). "The physics, biophysics, and technology of photodynamic therapy". Physics in Medicine and Biology 53 (9): R61–R109. doi:10.1088/0031-9155/53/9/R01. PMID 18401068.
12. ^ Lee, Tammy K; Elma D Baron, Thomas H Foster (2008). "Monitoring Pc4 photodynamic therapy in clinical trials of cutaneous T-cell lymphoma using noninvasive spectroscopy". Journal of Biomedical Optics 13 (3): 030507. doi:10.1117/1.2939068. PMC 2527126.PMID 18601524.
13. ^ Foster, TH; BD Pearson, S Mitra, CE Bigelow (2005). "Fluorescence anisotropy imaging reveals localization of meso-tetrahydroxyphenyl chlorin in the nuclear envelope.". Photochemistry and Photobiology 81 (6): 1544–1547. doi:10.1562/2005-08-11-RN-646.PMID 16178663.
14. ^ Wilson, JD; CE Bigelow, DJ Calkins, TH Foster (2005). "Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling.". Biophysical Journal (Biophysical Society) 88 (4): 2929–2938. doi:10.1529/biophysj.104.054528. PMC 1305387.PMID 15653724.
15. ^ Mellish, Kirste; Russell Cox, David Vernon, John Griffiths, Stanley Brown (2002). "In Vitro Photodynamic Activity of a Series of Methylene Blue Analogues". Photochemistry and Photobiology (American Society for Photobiology) 75 (4): 392–397. doi:10.1562/0031-8655.PMID 12003129.
16. ^ http://cat.inist.fr/?aModele=afficheN&cpsidt=18046718 "Synthesis, characterization and preclinical studies of two-photon- activated targeted PDT therapeutic triads" 2006
17. ^ http://www.ncbi.nlm.nih.gov/pubmed/15249365 "Selective photodynamic therapy by targeted verteporfin delivery to experimental choroidal neovascularization mediated by a homing peptide to vascular endothelial growth factor receptor-2." July 2004
18. ^ http://www.nature.com/bjc/journal/v95/n2/full/6603241a.html "Intracellular chemiluminescence activates targeted photodynamic destruction of leukaemic cells" 2006
19. ^ http://clinicaltrials.gov/ct2/show/NCT00706433?term=photodynamic+therapy&cond=acne&rank=1

External links

• Photochemical and Photobiological Sciences
• 'TV Cancer treatment' - Article on physics.org, February 2009