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

• Published in: Inorganic chemistry Vol. 53; no. 9; pp. 4548 - 4559
• Main Authors: Yin, Huimin, Stephenson, Mat, Gibson, Jordan, Sampson, Eric, Shi, Ge, Sainuddin, Tariq, Monro, Susan, McFarland, Sherri A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.05.2014
• Subjects: DNA - drug effects; HL-60 Cells; Humans; Photochemotherapy; Proton Magnetic Resonance Spectroscopy
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic5002368

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 in vitro 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 in vitro 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 in vitro 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).