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Photodynamic cancer therapy
Photodynamic therapy (PDT) is a revolutionary medical technology which is providing an alternative form of cancer therapy in a non-surgical, minimally-invasive way.
At the core of the technique is a photosensitizing drug which is activated by specific wavelengths of light. When this reaction occurs, the drug becomes cytotoxic producing an activated species of oxygen, singlet oxygen, which has the potential to kill cells in close proximity. These drugs are ideal for anti-cancer treatment because they are preferentially retained by tumour cells.
The photosensitising agent once injected into the bloodstream is absorbed by cells throughout the body. Within a short period of time, the drug selectively concentrates in diseased cells while largely clearing from normal tissue. Until exposed to laser light, the drug remains inactive. The wavelength of light used for PDT is in the red region of the visible spectrum, because red light penetrates more deeply into tissue than other wavelengths. Laser light is directed through a fiber optic which can be placed inside a bronchoscope for treating lung cancers, or through an endoscope for treating cancers of the oesophagus. Light from the laser then chemically activates the drug and creates a toxic form of oxygen which destroys the cancerous cells with minimal damage to healthy cells.
The laser light can only penetrate tissues to a depth of about 3 centimetres, meaning that for current methods in use, PDT is only being used to treat tumours close to the skin or those close to the lining of internal organs.
Photodynamic cancer therapy has advantages over surgery, radiography and chemotherapy because there are no life-threatening side effects involved with the therapy. The only side effect is that the patient has to stay in the dark for some time as part of the sensitizer can localise in healthy cells.
The major thrust of research in this fast developing field is towards the development of better photosensitising drugs with improvements in all of the following
criteria. The drugs must not be toxic in the absence of light. Drugs must show a greater selectivity for tumour cells compared to healthy cells and the drug must clear from healthy cells relatively rapidly so as to reduce skin photosensitivity. Preferred drugs would be those which possess a high photodynamic efficiency and photostability, and those which are activated at high wavelengths of light (in the red or near infrared region), as these allow for deeper tissue penetration and thus more effective tumour cell killing.
The most commonly used sensitizer in PDT is a haematoporphyrin derivative known as
Photofrin®. Photofrin® is also the only drug approved so far for PDT in North America, Japan, and the European Union. In the USA, Photofrin® is being used in PDT for the treatment of early and late stage lung cancer as well as advanced oesophageal cancer.
Photofrin® however only partially fulfils the above requirements and exhibits poor chemical and photophysical properties, with a low absorption coefficient in the red part of the spectrum. A promising new class of compounds are the phthalocyanines. The phthalocyanines demonstrate a much stronger absorption of red light than
Photofrin®, allowing more effective light penetration into tissues. Remarkable progress has been made over the years in the use of phthalocyanines as photosensitizers for photodynamic cancer therapy.
Designing improved derivatives of phthalocyanines for use as PDT drugs is an important focus of a research team at Rhodes University. This team is taking a multi-pronged approach to develop and improve on the efficacy of phthalocyanines as PDT drugs.
One aspect of their research explores how changing the metal at the centre of the phthalocyanine or altering the substituents attached to the metal or the phthalocyanine ring itself, alters the properties of these compounds for uses as PDT drugs. For example, placing diamagnetic metals such as aluminium or zinc at the centre of the phthalocyanines improves the photosensitization of the compound for use in PDT.
The phthalocyanines tend to aggregate in solution and this diminishes their photosensitising ability. The Rhodes team have shown success in solving this problem by designing phthalocyanines containing certain axial ligands for phthalocyanines containing the metals silicon, germanium and tin. It is however, important to develop a compound which is both water-soluble (for ease of drug administration) and fat soluble, for ease of transport through the body. Following up on this, the Rhodes team are designing what is known as unsymmetrically substituted phthalocyanines. Normally, phthalocyanines are designed with the same groups attached to the molecule (see the picture) to create a symmetrical compound. By attaching differing substituent groups, some of which are water soluble and some of which are fat soluble, an unsymmetrically substituted phthalocyanine is created which is both water and fat soluble. Showing much promise is a zinc phthalocyanine designed by the group. The zinc-substituted phthalocyanines produce sufficient amounts of reactive oxygen species required for tumour cell destruction making them highly suitable for use as PDT sensitizers.
A focal point in the developing field of PDT, is the design of drugs which can target specific cancers. This not only has an important role for use in PDT but may also aid in the early detection of
specific cancers. The Rhodes group is able to design specificity into their drugs by incorporating biological molecules during the synthesis of their drugs. For example, by attaching estrone to the phthalocyanine, produces a complex which will have specificity for areas of the body where estrone is found, such as in the breasts. This places these drugs in a prime position for future drug development for PDT targeting breast cancers.
The Rhode team is working in collaboration with Imperial College, London and will develop and test several new drugs for PDT.
PDT has not yet been accepted for use in treating cancers in Africa. Scientists are however forging ahead with the design of new light delivery devices and new photosensitising drugs and are exploring the use of PDT for treating a wider range of cancers of the skin, brain and reproductive organs. We will keep you updated.
The Rhodes team is headed by Professor Tebello Nyokong. MSc and PhD students designing PDT drugs are Pulane Matlaba, Suzanne Maree and David Maree. This article was prepared by Janice Limson with the assistance of Pulane Matlaba and Prof Tebello Nyokong. Please direct all enquiries to
editor@scienceinafrica.co.za
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