<i>In Vitro</i> Multiwavelength PDT with ³IL States: Teaching Old Molecules New Tricks

Abstract

The purpose of the present investigation was to ascertain whether ³IL excited states with microsecond lifetimes are universally potent for photodynamic applications, and if these long-lived states are superior to their ³MLCT counterparts as <i>in vitro</i> PDT agents. A family of blue-green absorbing, Ru­(II)-based transition metal complexes derived from the π-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 ³IL excited states photocleaved DNA with blue, green, red, and near-IR light. This panchromatic photodynamic effect translated to <i>in vitro</i> multiwavelength photodynamic therapy (PDT) with red-light cytotoxicities as low as 1.5 μM (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 ³IL 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 5 times more potent than Photofrin with therapeutic indices 30 times greater. Related Ru­(II) complexes having lowest-lying ³MLCT states of much shorter duration (≤1 μs) did not yield DNA photodamage or <i>in vitro</i> PDT with red or near-IR light, nor did the corresponding Os­(II) complex with a submicrosecond ³IL excited state lifetime. Therefore, metal complexes that utilize highly photosensitizing ³IL excited states, with suitably long lifetimes (≫ 1 μs), 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)