This blog post examines the principles and mechanisms of photodynamic therapy, where light, photosensitizers, and oxygen interact to target specific cells, providing a detailed explanation of how selective cell death occurs.
In the early 20th century, pharmacologist Tapiner accidentally observed that protozoa stained with leucoacridine dye died when exposed to lightning. He then confirmed that applying eosin, a fluorescent substance, to skin tumors and exposing them to light caused the tumors to react. Subsequent researchers elucidated that cells undergo death through the interaction of light, chemicals, and oxygen. Tapiner reported this phenomenon as an oxygen-dependent photoreaction and was the first to use the term “photodynamic therapy.”
Light energy, photosensitizers, and oxygen are essential for photodynamic therapy. When light of a specific wavelength is applied externally, the photosensitizer reacts with oxygen present around cells and tissues, locally generating reactive oxygen species (ROS) within a very short time. These ROS oxidize biomolecules, destroying their function and causing cell death. It is noteworthy that the wavelength of light required to maximize ROS generation—that is, the color—varies depending on the type of photosensitizer. This is because each photosensitizer reacts most efficiently to a specific wavelength. When activated by light of a specific wavelength, the photosensitizer transfers electrons or energy to surrounding oxygen, generating ROS. ROS also occur naturally in cellular metabolic processes. While beneficial in small amounts for biochemical reactions, excessive and prolonged production can become toxic, necessitating the administration of antioxidants to eliminate them.
The reactive oxygen species generated by irradiating the photosensitizer with light have an extremely short half-life of approximately 0.05µs or less, rapidly decaying immediately after formation. Their effective influence extends only about 20nm from the point of generation, causing a localized reaction only in the immediate vicinity of the photosensitizer.
Photosensitizers used in photodynamic therapy are categorized into porphyrin compounds and other fluorescent staining reagents. Since acne bacteria synthesize porphyrins themselves, exposing them to light of a specific wavelength selectively kills only the acne bacteria, enabling effective treatment. Many fluorescent dyes also possess the ability to release ROS and can be used as photosensitizers. However, they must release sufficient ROS upon light exposure, exhibit low toxicity when not exposed to light, and be readily excreted from the body. The therapeutic efficacy of photodynamic therapy is limited if externally applied light cannot penetrate deeply into the body. Treatment efficiency varies depending on the concentration of the photosensitizer, the intensity and duration of light exposure, and the oxygen concentration within the tissue. Furthermore, fluorescent substances that absorb light of specific wavelengths and emit longer wavelengths may exist within cells. Therefore, the wavelength of the photosensitizer and the light used to activate it must be selected while considering potential interference effects. Injecting high concentrations of photosensitizer can induce allergies. Furthermore, if photosensitizer that has not been broken down or excreted remains in the body, skin cells may be damaged upon exposure to sunlight. Therefore, light-blocking management is necessary until the residual photosensitizer is completely broken down.
Photodynamic therapy is currently widely used for treating various skin diseases and is also known to be effective in cancer treatment. For cancer treatment, it utilizes the mechanism where photosensitizers selectively accumulate in cancerous tissue. Photosensitizers administered intravenously are mostly insoluble in water and strongly bind to low-density lipoprotein (LDL) in the blood. Since cancer cells have a large number of LDL receptors on their cell membranes that bind to LDL, the photosensitizer accumulates more in cancer cells than in normal cells. During photodynamic therapy, damage to cancer tissue induces inflammation, which can activate the immune response against cancer cells, thereby enhancing treatment efficacy. While chemotherapy and radiation therapy cause severe side effects due to their strong toxicity, photosensitizers selectively accumulate only in cancer tissue and exhibit localized toxicity only at the light-irradiated site, making them a promising alternative cancer treatment.
