My research interests lie in the broadly defined areas of photochemistry and photobiology. The main objective of my research program is the development of new modalities of cancer treatment based on selective targeting of neoplastic tissue with highly cytotoxic free radicals and electronically excited species. This work is multi-disciplinary and lies at the chemistry-biology interface. The overall research design borrows modern experimental techniques and theories from fields such as physical-organic photochemistry, biophysics, biochemistry, and cell biology. Current research focuses primarily on the concepts of mitochondrial targeting and enzyme-directed prodrug therapy.
The observation that enhanced mitochondrial transmembrane potential is a prevalent cancer cell phenotype has provided the conceptual basis for the development of mitochondrial targeting as a novel therapeutic strategy for both chemo- and photochemotherapy of neoplastic diseases. Because the plasma transmembrane potential is negative on the inner side of the cell, and the mitochondrion transmembrane potential is negative on the inner side of this organelle, extensively conjugated cationic molecules, i.e. cationic dyes, displaying appropriate structural features are electrophoretically driven through these membranes and tend to accumulate inside energized mitochondria. In keeping with the higher mitochondrial transmembrane potential typical of tumor cells, a number of cationic dyes have been found both to accumulate in larger amounts and to be retained for much longer periods in the mitochondria of these cells as compared to normal cells. Moreover, the phototoxic effects associated with some of the cationic dyes known to accumulate in mitochondria were found to be much more pronounced in tumor cells than in normal cells. The structural determinants of the specific accumulation of certain cationic species into cell mitochondria are not entirely understood though, and the lack of a model to describe the relationship between the molecular structure of these dyes and their disproportionate accumulation in tumor-cell mitochondria has prevented mitochondrial targeting from becoming a more dependable therapeutic strategy. We are currently working on the development of a reliable model to guide the design of new drugs for selective and effective photochemical destruction of tumor cells via mitochondrial targeting. To this end, we are currently investigation how the molecular structure of extensively conjugated cationic molecules affect their cellular uptake, subcellular distribution, and ultimately mitochondrial accumulation. While our biological models provide information on the structural determinants of subcellular localization, our photochemical investigations provide information on the determinants of dye phototoxicity (or drug potency).
The concept of enzyme-directed prodrug therapy is based on the enzymatic generation of highly cytotoxic species in targeted tissues from substrates (prodrugs) that ideally show just minor or negligible systemic toxicity. The success of this concept in tumor therapy depends, to a large extent, on the identification of enzymes that are over-expressed in cancer cells. However, the targeting of cancer cells with antibody-enzyme conjugates can also provide the therapeutic window required for the selective and effective destruction of tumors. This last strategy is known as antibody-directed enzyme-prodrug therapy (ADEPT). We are currently screening libraries of putative precursors of highly cytotoxic products in reactions catalyzed by model activation enzymes in an effort to identify novel classes of enzymes and prodrugs for use both in ADEPT and in enzyme-directed prodrug therapy.