In Vitro Multiwavelength PDT with 3IL States: Teaching Old Molecules New Tricks

The purpose of the present investigation was to ascertain whether (IL)-I-3 excited states with microsecond lifetimes are universally potent for photodynamic applications, and if these long-lived states are superior to their (MLCT)-M-3 counterparts as in vitro PDT agents. A family of blue-green absorbing, Ru(II)-based transition metal complexes derived from pi-expansive dppn ligand was prepared and characterized according to its photodynamic activity against HL-60 cells, and toward DNA in cell-free media. Complexes in this series that are characterized by low-energy and long-lived (IL)-I-3 excited states photocleaved DNA with blue, green, red, and near-IR light. This panchromatic photodynamic effect translated to in vitro multiwavelength photodynamic therapy (PDT) with red-light cytotmdcities as low as 1.5 mu M (EC50) for the parent complex and 400 nM for its more lipophilic counterpart. This potency is similar to that achieved with Ru(II)-based dyads containing long-lived (IL)-I-3 excitons located on appended pyrenyl units, and appears to be a general property of sufficiently long-lived excited states. Moreover, the red PDT observed for certain members of this family was almost S times more potent than Photofrin with therapeutic indices 30 times greater. Related Ru(II) complexes having lowest-lying (MLCT)-M-3 states of much shorter duration (<= 1 mu s) did not yield DNA photodamage or in vitro PDT with red or near-IR light, nor did the corresponding Os(II) complex with a submicrosecond (IL)-I-3 excited state lifetime. Therefore, metal complexes that utilize highly photosensitizing (IL)-I-3 excited states, with suitably long lifetimes (>> 1 mu s), are well-poised to elicit PDT at wavelengths even where their molar extinction coefficients are very low (<100 M-1 cm(-1)). Herein we demonstrate that such unexpected reactivity gives rise to very effective PDT in the typical therapeutic window (600-850 nm).