Chemical aspects of mitochondrial targeting in photodynamic therapy

The preferential uptake and retention of specific cationic dyes by tumor cell mitochondria has motivated the examination of mitochondrial targeting as a novel therapeutic strategy for both chemo- and photochemotherapy of neoplastic diseases. However, the structural determinants of the specific accumulation of certain cationic dyes into cell mitochondria are not well understood, and the lack of a robust 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. The objectives of this project were two-fold. First, to explore how the molecular structure of cationic triarylmethane photosensitizers modulate their subcellular distribution, mitochondrial accumulation, and ultimately selective phototoxicity towards tumor cells. Second, to explore mechanisms of photosensitization by mitochondrial dyes that might provide for photoinduced tumor cell destruction both in the presence and absence of oxygen. The photosensitizers that are currently in clinical use in photodynamic therapy do not work well in hypoxic or poorly perfused tumor areas, and the presence of such areas in solid tumors are thought to represent one of the major determinants of tumor recurrence in photodynamic therapy.; Our findings strongly suggest that selective phototoxicity towards tumor cells takes place only when the triarylmethane photosensitizer stains the mitochondria with a high degree of specificity. For the cases in which other subcellular compartments are simultaneously stained tumor selectivity is lost. These studies also suggest that tumor selectivity only takes place when the lipophilic/hydrophilic character of the cationic photosensitizer falls within a relatively narrow range and assumes a value close to that of the classical and highly specific mitochondrial marker Rhodamine-123. In addition, we have identified a mechanism of biopolymer damage upon photolysis of biopolymer-photosensitizer noncovalent complexes that is initiated by a photoinduced electron transfer event and does not require the involvement of oxygen to operate. These findings represent important guidelines for the development of new tumor-selective photosensitizers based on the concept of mitochondrial targeting.