Photomedicine

At present, the search for an effective combat of cancer is of great importance due to current treatment’s inability to discriminate between healthy and malignant cells. Alternative approaches such as photodynamic therapy (PDT) came to the forefront of medicinal methodology in the 1980’s at several institutions throughout the world and involve three key components: a photosensitizer, light, and tissue oxygen. The photosensitizer is used in conjunction with light to create a highly reactive singlet oxygen (1O2) species localized within the tumor cells. Singlet oxygen (a very aggressive chemical species) will rapidly react with any nearby biomolecules (with the specific targets depending heavily on the photosensitizer chosen) leading to destructive reactions resulting in cell destruction through apoptosis or necrosis.

Activation of these molecules occurs when the tumor is exposed to light of appropriate wavelength. The central challenge of our research in this field is to discover the appropriate photosensitizer that (1) has high intensity absorption in the right UV-vis region, (2) can be excited with a defined wavelength but also (3) possesses excellent invasion and localization properties towards tumor cells. The essential benefits offered by PDT are its minimal invasiveness, its potential for killing tumor cells in a locally confined area while not affecting healthy cells and the possibility for repetitive treatment.

Porphyrins are highly conjugated molecules with an extensive delocalized p-electron system absorbing strongly in the UV-visible region; this makes them one of the few chemical species suitable for PDT. Preliminary studies in the our group have shown that new compounds with an intramolecular dipole moment (so called push-pull fragments) combined with larger p-systems are suitable photosensitizers which absorb longer wavelengths and thus allow the treatment of larger tumors or the deeper penetration of the exciting light.

Synthetic methods previously developed within our group are being used for multiparallel porphyrin synthesis to design a target molecule series. A wide range of asymmetrically substituted arrays with mixed substituents (electronic and amphiphilic characters) are being synthesized and characterized. Developing these molecules will allow us to control charge transfer and separation, resulting in an increase of absorption intensity and to modulate the singlet oxygen quantum yield.

The future progress and the development of truly selective photosensitizers for PDT (minimum side effects and maximum affectivity) are critically dependent on the development of highly selective, targeted synthesis. Our research not only offers the development of potentially useful synthetic methodologies but also allows an entry into previously unexplored classes of porphyrin derivatives with unique combination of structural and spectroscopic properties.

Photodynamic therapy (PDT) is a clinically approved treatment for cancer and other non-malignant illnesses. Despite 20 years of research on the use of PDT as a treatment, surgery remains the gold standard for the treatment of esophageal cancer. In most patients the treatment with PDT is mostly palliative, however, all current treatment protocols have significant side effects or problems and accepted guidelines require a complementary use of these modalities. Nevertheless, the numerous studies already performed in this area probably offer a good basis to evaluate future developments with tailor-made and advanced drugs.

The ultimate goal of the project is to select and further develop a highly efficient amphiphilic photosensitizer with tailor-made photophysical and localization properties and to use these for investigations on the aetiology, indication and treatment of esophageal cancer. In the long term, the project will involve the development of a sensitive high content screening method coupled with short, efficient and general synthetic strategies for amphiphilic tetrapyrroles. The development of combinatorial porphyrin synthesis coupled with a characterization and optimization of their photophysical properties and detailed studies on their cellular localization properties and related uptake mechanisms. Furthermore the project will include cell biological studies on the aetiology of esophageal cancer and Barrett’s esophagus and finally the testing of the ability to effect cell death with minimal, if any bystander cell damage, and a differentiation between singlet oxygen induced tumor necrosis and photosensitizer mediated apoptosis.

In order to establish the validity of our approach the present project will be to examine novel photoactivatable compounds to determine whether they (1) Accumulate selectively in esophageal malignant or dysplastic cells. (2) Are photoactivatable to induce death of malignant cells.

In these studies we used esophageal adenocarcinoma cell lines currently in use in our laboratory including OE33 and SKGT-4 (derived from the Barrett’s adenocarcinoma) and OE21 (derived from a squamous carcinoma of mid esophagus). In addition, we studied, a non-malignant esophageal cell line, HET-1A.