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New Agent Boosts Prospects for Photodynamic Therapy

LONDON – Researchers trying to develop drugs that are more efficient at killing tumor cells when exposed to laser light have successfully identified compounds that are much more toxic than predecessors.

A study carried out jointly by PhotoBiotics Ltd., of London, and Imperial College London has pinpointed the importance of targeting the drugs to the mitochondria of tumor cells.
One of the new compounds identified may enter clinical trials in the UK to evaluate its use as a treatment for prostate cancer within two years.

Ultimately, the discovery could raise the profile of photodynamic therapy for cancer and, depending on the results of clinical trials, could allow more patients to benefit from this type of treatment.
Mahendra Deonarain, reader in antibody technology at Imperial College London, told BioWorld International: "This is an important finding because photodynamic therapy is underutilized. It is a gentle therapy and has few side effects. Although you have to be able to shine a laser on the tumor, this is often possible as many cancers are localized."
In conventional photodynamic therapy for cancer, the patient is given a photosensitive drug that spreads throughout the body.

However, PhotoBiotics has developed a method of conjugating the drug to an antibody fragment that can help to target it specifically to the tumor. Shining a high-powered cold laser light onto the tumor causes the drug to undergo a photochemical reaction with the release of singlet oxygen. The latter is highly reactive, killing the cells in which it appears, but also very short lived, so that there is little collateral damage to the surrounding tissues.

"Photodynamic therapy is an approved treatment in the UK National Health Service, and it has been used, for example, to successfully treat some patients with head and neck cancer," Deonarain said. "But one of the problems is that the photosensitizing drugs that are used do not localize to the tumor as much as we would like. In addition, they stay in the body for several weeks, so that patients remain highly sensitive to light and can experience sunburn-like reactions from light."

Researchers at PhotoBiotics, a spinout company from Imperial College London, working with colleagues at Imperial College London, set out several years ago to improve on an existing photosensitive agent, called PPa, which is derived from chlorophyll. The researchers wanted to make a version of PPa that was more water-soluble because hydrophilic drugs wash out of the body more quickly.

They tried two ways of achieving that: adding chemical groups that they thought would make PPa more soluble (while remaining electrically neutral) and adding an electrical charge to the molecule. They then incubated the photosensitizing drugs with tumor cells.
Using confocal microscopy – a method that makes it possible to view slices through whole cells – coupled with fluorescence technology, Deonarain and his colleagues were able to see that the electrically neutral version of the new drugs localized in the mitochondria of the tumor cells, while the charged version remained in the cytoplasm.

Other experiments showed that the neutral compound was 13 times more phototoxic than PPa to ovarian cancer cells in culture, while the electrically charged compound was 18 times less phototoxic than PPa.
An account of the findings appeared in Photochemical and Photobiological Sciences.
"In further studies soon to be published, we have linked the neutral compound to an antibody and have shown that it can kill tumors in an animal model of cancer," Deonarain said. "We also have preliminary data from treating an animal model of prostate cancer. But we have also shown that the electrically charged compound is extremely good at producing singlet oxygen so we are working on modifying this so that we can target it at the appropriate part of the cell."

The research has shown, he added, that it is important not just to target the photosensitizing drugs at the tumor cells, but also to ensure that they reach the correct compartment within cells.
Production of singlet oxygen in the mitochondria – where the process of apoptosis is known to begin – is much more damaging to the tumor cells than when it occurred in the cytoplasm.

David Phillips, emeritus professor at Imperial College, a founder of PhotoBiotics and one of the paper's principal authors, said, "Ultimately, this work helps us to design more potent and specifically targeted photodynamic therapy agents. To ensure that photosensitizing drugs locate specifically to tumor cells, we are now concentrating on so-called third-generation photodynamic therapy involving the specific targeting of PhotoBiotics' photosensitizing drugs to lipid-rich organelles in tumors via PhotoBiotics' unique Optilink conjugation technology, utilizing single-chain antibody fragments."