OXYGEN SENSITIZERS FOR PHOTODYNAMIC INACTIVATION AND MECHANISTIC STUDIES

In order to minimize undesired side effects, including damage to healthy tissue during Photodynamic therapy (PDT) treatment, photosensitization of 1O2 is controlled via the specific targeting of the photosensitizer to ailing over healthy tissue and through the precise delivery of the exciting light. Recently the chemical activation of an otherwise dormant photosensitizer specifically in the targeted tissue has emerged as an effective new level of control. The method exploits differences in the proteome or metabolome of an ailing tissue over the healthy tissue. Here I will describe the design of new dormant sensitizers that activate under oxidative stress or in the presence of cellular nucleophiles. These compounds are based on two-segment photosensitizer-trap molecules where the photosensitizer segment consists of a Br-substituted BODIPY dye. For activation via oxidative stress the trap segment consists of the chromanol ring of α-tocopherol, the most potent naturally occurring lipid soluble antioxidant. Photoinduced electron transfer to either the singlet or triplet excited state of the BODIPY core leads to deactivation of the dye. Following ROS scavenging, the probe becomes active. In turn, for activation by cellular nucleophiles, the compound incorporates a reactive acrolein warhead. The acrolein moiety serves as an intramolecular switch, deactivating the BODIPY dye in its singlet and triplet excited states via internal conversion. Reaction with cysteine residues restores the photosensitizing properties. Time-resolved absorption, fluorescence, and 1O2 phosphorescence studies together with fluorescence and 1O2 phosphorescence emission quantum yields and DFT studies support these mechanisms.The usefulness to selectively activate the production of singlet oxygen will be described both in therapeutic applications and mechanistic studies involving photodynamic inactivation of Gram negative E.coli strains and in HeLa cell studies.  

This work was supported by Natural Sciences and Engineering Research Council of Canada and by the Canada Research Chairs Program.