Mesothelioma

Photodynamic therapy is based on a series of chemical reactions involving a specific wavelength of visible light, a photosensitizing drug, and oxygen. There is no standard wavelength of light, light source, exposure period, or method of administering the medication that covers all forms of PDT. Most photosensitizing drugs are given intravenously, but some are applied to the skin or taken by mouth. Photosensitizers given by injection are activated by light in the red portion of the visible light spectrum, around 630–700 nanometers (nm; a nanometer is a measure of length, one billionth of a meter), while those applied to the skin are usually activated by blue light.

In general, cancerous tumors inside the body need more concentrated doses of light than abnormal growths on the body surface. Lasers are usually used to deliver highly concentrated light at one specific wavelength, while light sources that provide a larger area of illumination, such as light-emitting diodes (LEDs), are more efficient for treating skin tumors.

In contrast to their uses in surgery, lasers are not used in PDT to remove tissue or seal blood vessels with heat; rather they are used to start a chemical reaction. As a result, they do not become hot enough to burn tissue. The burning or stinging sensation that some patients experience during PDT is caused by the release of oxygen stimulating nearby nerve endings rather than heat from the laser itself.

Lasers can be attached to fiberoptics for treating tumors inside the body. Fiberoptics are thin strands of plastic or glass with special optical properties that can be threaded through a bronchoscope or endoscope, which are special tubes that allow the doctor to see into the patient’s lungs or esophagus. Light from the laser is then transmitted along the special fibers to the tumor, thus allowing the doctor to activate the photosensitizing medication in a very small area of tissue without damaging normal tissue nearby.

PDT is a two-step form of therapy. First, the photosensitizing medication is injected into a vein or applied to the skin several days or hours before the scheduled treatment. The drug is absorbed by all body tissues but remains in cancer cells longer than in normal cells because the cancer cells are multiplying faster. After the medication has had time to collect in the malignant cells, the doctor directs a light source of the proper wavelength on the targeted area. When the light source strikes tissue containing the photosensitizing medication in the presence of oxygen, the medication is activated and produces free radicals and a highly reactive form of oxygen called singlet oxygen. The free radicals and singlet oxygen interact with the cell membranes of the cancer cells to destroy the energy-producing structures inside the cancer cells. In addition to killing the cancer cells directly, PDT works by closing blood vessels inside the tumor, thereby shutting off its supply of nutrients, and by stimulating the immune system to produce interleukins (nonantibody proteins) and other substances that attack the 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) is applied.
• A waiting period of a few hours is allowed to elapse, during which time
o ALA will be taken up by cells, and
o 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.
o Protoporphyrin IX absorbs light, exciting it to an excited singlet state;
o Intersystem crossing occurs, resulting in excited triplet protoporphyrin IX;
o Energy is transferred from triplet protoporphyrin IX to triplet oxygen, resulting in singlet (ground state) protoporphyrin IX and excited singlet oxygen;
o 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.

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.

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.

A major disadvantage 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 because of the same reason.

Photodynamic therapy (PDT), matured as a feasible medical technology in the 1980s at several institutions throughout the world, is a ternary 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. The German physician Friedrich Meyer–Betz performed the first study with photodynamic therapy (PDT) with porphyrins in humans in 1913. Meyer–Betz tested the effects of haematoporphyrin-PDT on his own skin. Modern day versions of it were tested at the Mayo Clinic and Roswell Park Cancer Center, but did not really become widespread until Thomas Dougherty initiated clinical trials and formed the International Photodynamic Association, in 1986.

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 result in cell killing through apoptosis or necrosis.