Role of photoproducts in the cytotoxic action of selenomerocyanine-mediated photodynamic therapy

Many Type II photosensitizers are substrates of the singlet oxygen they generate. They are, therefore, converted to photoproducts when exposed to light in the presence of oxygen. While most photoproducts appear to be biologically inert, one of the photoproducts generated by selenomerocyanine photosensitizers is a form of elemental selenium that is surprisingly toxic to tumor cells if allowed to form conjugates with serum albumin or lipoproteins. Albumin and lipoproteins act as delivery vehicles for the cytotoxic entity, exploiting the fact that many tumor cells have an increased capacity to bind and internalize albumin and/or lipoproteins. The cytotoxic mechanism of Se(0)-protein conjugates is not yet fully understood but is obviously quite different from the singlet oxygen-mediated mechanism of merocyanine-mediated photodynamic therapy (PDT). Whereas merocyanine-PDT is directed against the plasma membrane, is more effective at 4 °C than at room temperature, and is inhibited by excess albumin and lipoproteins, selenomerocyanine-derived cytotoxic photoproducts act on intracellular targets, are ineffective at low temperatures, and require albumin or lipoproteins as carrier molecules. The discovery of cytotoxic Se(0)-protein conjugates provides a rare example of photoproducts contributing substantially to the cytotoxic effect of PDT and challenges the widely held notion that elemental selenium is biologically inert.