The process of photosynthesis underpins the existence and maintenance of life on Earth. For a long time, scientists have tried to harness the powerful mechanisms that underpin the process and turn them loose on disease through a discipline known as photodynamic therapy.
Photodynamic therapy combines a chemical consisting of light-sensitive molecules called a photosensitizer and a light source. When light of a certain wavelength is aimed at a photosensitizer it releases highly reactive singlet oxygen radicals, which produce chemical reactions that can damage or kill cells. Though most well known as a treatment for acne, photodynamic therapy has also been used to target cancerous tumours in the oesophagus, lungs and other parts of the body that are near enough to the surface of the skin so that light can penetrate.
At the Weizmann Institute of Science in Rehovot, Israel, a new photodynamic therapy has been developed that could revolutionise the treatment of early stage prostate cancer and perhaps lead to a rethink in how photodynamic therapy is carried out across the board. Non-invasive, with none of the side effects of prostate removal surgery or radiotherapy, and taking only 90 minutes to carry out, the treatment has just passed Phase III clinical trials and received approval in Mexico, with approval also pending in Europe.
A team led by Professor Yoram Salomon at the Biological Regulation Department and Avigdor Scherz of the Plant and Environmental Sciences Department developed a new photosensitizer known as Tookad Soluble, which is synthesised from bacteriochlorophyll, a photosynthetic agent that derives from a type of aquatic bacteria. In clinical trials, patients were put under general anaesthetic then administered the drug intravenously, the dose dependent on prostate size. Hollow, transparent catheters were placed in the prostate and cylindrically diffusing optical fibres inserted within, directing the beam of a 753 nanometre laser.
Men aged 18 and over diagnosed with localised prostate cancer were recruited for the study, with anyone who had received prior treatment for cancer excluded. At six months, 61 of the 83 patients who underwent the procedure tested negative for prostate cancer, showing that in 74% of cases the drug combined with the light had destroyed all of the cancerous tissue.
Photodynamics: new materials needed
The development of this therapy has been more than 20 years in the making. At the time, Scherz was studying the way that chlorophylls and bacteriochlorophylls converted solar energy into electrical energy but illness in the family made him turn his attention to cancer research.
"In the late 1980s and early 90s the contemporary way of treating cancer – chemotherapy, radiotherapy – had to be changed," he says. "I thought there must be an alternative to these methodologies. I looked at what I could do and the field of photodynamic therapy was quite familiar to me, but I felt there were a lot of wrong things done in this field."
The main problem Scherz identified was that the most commonly used photosensitizer was a chlorophyll-like molecule, which is still the most commonly used type of agent today. Although these types of molecules had some of the necessary properties to carry out successful photodynamic therapy, they contain flaws which make them struggle to do everything that’s required of them.
"The problem is that chlorophylls are molecules that have been designed by nature to do everything except be activated by light in the body," he says. "Because otherwise they would not exist – they would be burned by the sunlight and peel everywhere… Nature provided them with relatively small absorption and high oxidation potential so they cannot transfer electrons to oxygen as energy [the energy that creates the chemicals that kill cancer cells].
"The attempt was made to try to intoxicate individual cancer cells, to get something that will accumulate better within the cancer cells than in the normal tissue. The difference between accumulating in the cancer cells and the surrounding tissue was not sufficient to provide selectivity."
Replicating natural processes in cancer battle
The Tookad team decided to use bacteriochlorophylls instead. They had similar qualities but much greater ability to absorb sunlight and they also performed well when crossed with light in the 750-820 nanometre range, the most potent at penetrating human tissue. Now with a more suitable photosensitizer the team would try to overcome the problem of selectivity by mimicking mechanisms seen in the natural world, where distressed plants create oxygen radicals that help to shed malfunctioning organs, the tumour in this case being the equivalent of that organ.
"Sometimes you see there are white spots on the leaves of plants and shortly afterwards these leaves are shed – you think it’s because of the bugs that feed on the leaves and kill them," Scherz explains. "It’s the other way around actually. The plants sacrifice these leaves in order to survive. We’ve seen this phenomenon in humans and animals in the case of [the onset of] sepsis, which is followed by the collapse of an intestine or of a lung. The mechanism of this process is the pulse generation of oxygen and nitric oxide radicals [the same ones that help destroy tumour cells]. With animals it’s in the circulation due to the activation of white blood cells, in plants it’s for other reasons but well-localised in the leaf that is malfunctioning."
Moving the bacteriochlorophylls from the plant to the animal milieu made them unstable and meant that their chemical composition needed tweaking. It took 200 different molecule combinations to finally get a drug that has worked so well in trials. Tookad Soluble is now set to undergo another series of trials in partnership with the Memorial Sloan Kettering Hospital in New York that will combine the treatment with immune modulation therapy. The hope is that this can improve the effectiveness of the treatment or even help the body develop immunity to tumours.
"When we combine this approach with immune modulation, we should be able to treat a more advanced form of prostate cancer as well as oesophageal cancer, breast cancer and others."