Photodynamic therapy (PDT) is a form of phototherapy using nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they target malignant and other diseased cells. Each photosensitizer is activated by light of a specific wavelength. Thus, doctors use specific photosensitizers and wavelengths of light to treat different areas of the body with PDT. PDT has proven ability to kill microbial cells, including bacteria, fungi and viruses. PDT is used clinically to treat a wide range of medical conditions, including wet age-related macular degeneration, malignant conditions, cancers, acne and is recognised as a treatment strategy which is both minimally invasive and minimally toxic.
The combination of light and a photosensitizer leads to the chemical destruction of those tissues which have selectively taken up the photosensitizer and have been locally exposed to light. The wavelength of the light source needs to be appropriate for exciting the photosensitizer to produce reactive oxygen species (ROS). These reactive oxygen species are generated through electron abstraction under the light influence, are highly reactive state of oxygen known as singlet oxygen (Type II PDT). In understanding the mechanism of PDT it is important to distinguish it from other phototherapy procedures, such as laser wound healing, pain and SAD light therapy which do not require a photosensitizer.
PDT Laser Therapy
In order to achieve the selective destruction of the target area using PDT while leaving normal tissues untouched, either the photosensitizer can be applied locally to the target area, or photosensitive targets can be locally excited with light. For instance, in the treatment of skin conditions, including acne, psoriasis, and also skin cancers, the photosensitizer can be applied topically and locally excited by a light source.
In the local treatment of internal tissues and cancers, after photosensitizers have been administered intravenously, light can be delivered to the target area using endoscopes and fiber optic catheters.
Photosensitizers can also target many viral and microbial species, including HIV and MRSA. Using PDT pathogens present in samples of blood and bone marrow can be decontaminated before the samples are used further for transfusions or transplants. PDT can also eradicate a wide variety of pathogens of the skin and of the oral cavities. Given the seriousness that drug resistant pathogens have now become, there is increasing research into PDT as a new antimicrobial therapy.
PDT Therapy Mechanism
A photosensitizer is a chemical compound that can be promoted to an excited state upon light absorption; it undergoes intersystem crossing with oxygen to produce singlet oxygen. This species rapidly attacks any organic compounds it encounters, thus being highly “cytotoxic”. Photosensitizers have a short lifetime and are rapidly eliminated: in cells, the average lifetime is 3 µs.
Photosensitizers for PDT can be divided into:
Some examples of photosensitizers include:
- Aminolevulinic acid (ALA)
- Silicon Phthalocyanine Pc 4
- M-tetrahydroxyphenylchlorin (mTHPC)
- Mono-L-aspartyl chlorine 6 (NPe6)
Several photosensitizers are commercially available for clinical use, such as:
Others are in development, such as
Antrin, Photochlor,Photosens, Photrex, Lumacan, Cevira, Visonac, BF-200 ALA, Amphinex, Azadipyrromethenes.
Although these photosensitizers can be used for wildly different treatments, they all aim to achieve certain characteristics:
- High absorption at specific wavelengths
- Tissue is much more transparent at longer 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 photo-bleaching to prevent degradation of the photosensitizer so it can continue producing singlet oxygen
- Natural fluorescence
- Many optical dosimetry techniques, such as fluorescence spectroscopy depend on the product being naturally fluorescent
- 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 m-THPC has been shown to localize in the nuclear envelope; in contrast, ALA has been found to localize in the mitochondria and Methylene Blue in the lysosomes.
To allow treatment of deeper tumours some researchers are using internal chemo luminescence to activate the photosensitizer.
PUVA therapy is using psoralen as photosensitizer and UVA ultraviolet as light source, but this form of therapy is usually classified as a separate form of therapy from photodynamic therapy.
PDT and Photosensitizers
Some photosensitizers naturally accumulate in the endothelial cells of vascular tissue allowing “vascular targeted” PDT, but there is also research to target the photosensitizer to the tumour (usually by linking it to antibodies or antibody fragments). It is currently only in pre-clinical studies.Most types of cancers are especially active in both the uptake and accumulation of photosensitizer’s agents, which makes cancers especially vulnerable to PDT.
While the applicability and potential of PDT has been known for over a hundred years, the development of modern PDT has been a gradual process, involving scientific progress in the fields of photobiology and cancer biology, as well as the development of modern photonic devices, such as lasers and LEDs. It was John Toth, product manager for Cooper Medical Devices Corp/Cooper Lasersonics, who acknowledged the “photodynamic chemical effect” of the therapy and wrote the first “white paper” branding the therapy as “Photodynamic Therapy” (PDT) 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.
In the 1990s the team of Polish professor Aleksander Sieroń developed the process and devices used today for PDT treatment, while improving the photosensitizer compound at the university of Bytom in Poland. This Polish team is considered at the cutting edge of research in this field, with many published articles and ongoing clinical trials.
Of all the nations beginning to use PDT in the late 20th century, the Russians were the quickest to advance its use clinically and to make many developments. One early Russian development was a new photosensitizer called Photogem which, like HpD, was derived from haematoporphyrin in 1990 by Professor Andrey F. Mironov and coworkers in Moscow. Photogem was approved by the Ministry of Health of Russia and tested clinically from February 1992 to 1996. A pronounced therapeutic effect was observed in 91 percent of the 1500 patients that underwent PDT using Photogem, with 62 percent having a total tumor resolution. Of the remaining patients, a further 29 percent had a partial tumor resolution, where the tumour at least halved in size. In those patients that had been diagnosed early, 92 percent of the patients showed complete resolution of the tumour.
PDT has also seen considerably development in Asia. Since 1990, the Chinese have been developing clinical expertise with PDT using their own domestically produced photosensitizers, derived from Haemato-porphyrin, and light sources.PDT in China is especially notable for the technical skills of specialists in developing procedures to reach difficult treatable tumours.
Around this time, Russian scientists also collaborated with NASA medical scientists who were looking at the use of LEDs as more suitable light sources, compared to lasers, for PDT applications.
This opinion did change in last 5 years, especially based on development and clinical trials work done in Germany.
Blood irradiation therapy
Blood irradiation is a procedure in which the blood is exposed to low level red light (often laser light) for therapeutic reasons. Most research on blood irradiation therapy has been conducted in Germany, Russia and China, while smaller-scale research has been performed in other countries such as Britain. Blood irradiation therapy can be administered through a catheter in a vein, through the blood vessels inside the nose or applied externally through the skin. It is not related to the practice of gamma irradiation of blood in transfusion medicine. Intravenous laser blood irradiation was developed experimentally by the Russian researchers, Meshalkin and Sergievskiy, and introduced into clinical practice in 1981. Originally the method was successfully applied in the treatment of cardiovascular abnormalities.
Intravenous or intravascular blood irradiation involves the in-vivo illumination of the blood by feeding low level laser light generated by a 1–3 mW laser at originally a wavelength of 632.8 nm into a vascular channel, usually a vein in the forearm, under the assumption that any therapeutic effect will be circulated through the circulatory system. The feasibility of intravascular laser irradiation for therapy of cardio-circulatory diseases was first presented in the American Heart Journal in 1982.
Ultraviolet blood irradiation may also be applied, though it involves drawing blood out through a vein and irradiating it outside of the body. Though promoted as a treatment for cancer, a 1952 review in the Journal of the American Medical Association and another review by the American Cancer Society in 1970 concluded the treatment was ineffective.
European Platform for Photodynamic Medicine (EPPM) is a platform attended by members from academia, hospitals, research centres and industry. One important goal of EPPM is to facilitate the transfer of knowledge and technology between academia and industry in order to rapidly bring innovations in photodynamic medicine to cancer patients.
- Cancer therapy
- Skin dermatological issues
- Acne therapy
- Intra-articular arthrosis, osteoarthritis therapy
- Fat and Cellulite reduction
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