Proof-of-principle for two-stage photodynamic therapy: hypoxia triggered release of singlet oxygen

We propose to overcome oxygen deficiency and light attenuation problems in photodynamic therapy (PDT), by separating photo-excitation and singlet oxygen delivery of the PDT process into two distinct operations to be carried out sequentially, at different locations. We now demonstrate the viability of this approach, using 2-pyridone derivative which yields a relatively stable endoperoxide. The initial storage endoperoxide obtained is transformed enzymatically into a more labile compound when placed in hypoxic cell cultures, and releases singlet oxygen significantly faster. The potential of this approach in advancing PDT beyond its current limits is exciting.