Levulan Photodynamic Therapy

Photodynamic therapy

Photodynamic therapy (PDT), matured as a feasible medical technology in the 1980s at several institutions throughout the world, is a third-level treatment for cancer involving three key components: a photosensitizer, light, and tissue oxygen. It is also being investigated for treatment of psoriasis and acne, and is an approved treatment for wet macular degeneration.

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.

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.

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 the International Photodynamic Association, in 1986.

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 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. (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)) 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.

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.

Advantages and limitations

Unlike chemotheraphy 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. In our example, ALA was only applied to the area to be treated.
  • 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. Thus the application of PDT is 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 since about 2007 hollow needles have been used by some units to get the light into deeper tissues.

Photosensitizers

A wide array of photosensitizers for PDT exist. Some examples include aminolevulinic acid (ALA), Silicon Phthalocyanine Pc 4, m-tetrahydroxyphenylchlorin (mTHPC), and mono-L-aspartyl chlorin e6 (NPe6). Several photosensitizers are also commercially available, such as Photofrin, Visudyne, and LS11. 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 higher 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
  • 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 cell walls.

See also

References

External links

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