Ru(II) CONTAINING PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY: A CRITIQUE ON REPORTING AND AN ATTEMPT TO COMPARE EFFICACY

Abstract

Ruthenium(II)-based coordination complexes have emerged as photosensitizers (PSs) for photodynamic therapy (PDT) in oncology as well as antimicrobial indications and have great potential. Their modular architectures that integrate multiple ligands can be exploited to tune cellular uptake and subcellular targeting, solubility, light absorption, and other photophysical properties. A wide range of Ru(II) containing compounds have been reported as PSs for PDT or as photochemotherapy (PCT) agents. Many studies employ a common scaffold that is subject to systematic variation in one or two ligands to elucidate the impact of these modifications on the photophysical and photobiological performance. Studies that probe the excited state energies and dynamics within these molecules are of fundamental interest and are used to design next-generation systems. However, a comparison of the PDT efficacy between Ru(II) containing PSs and 1^st or 2^nd generation PSs, already in clinical use or preclinical/clinical studies, is rare. Even comparisons between Ru(II) containing molecular structures are difficult, given the wide range of excitation wavelengths, power densities, and cell lines utilized. Despite this gap, PDT dose metrics quantifying a PS's efficacy are available to perform qualitative comparisons. Such models are independent of excitation wavelength and are based on common outcome parameters, such as the photon density absorbed by the Ru(II) compound to cause 50% cell kill (LD₅₀) based on the previously established threshold model. In this focused photophysical review, we identified all published studies on Ru(II) containing PSs since 2005 that reported the required photophysical, light treatment, and in vitro outcome data to permit the application of the Photodynamic Threshold Model to quantify their potential efficacy. The resulting LD₅₀ values range from less than 10¹³ to above 10²⁰ [hν cm^-3], indicating a wide range in PDT efficacy and required optical energy density for ultimate clinical translation.

Figure 1.

Schematic of Ru-coordination coordinates according to A) [55] for Ru-BP, B) [58] for 1, C) [66] for Ru-Pt and C) [67] for CHL-RuL.

Figure 2.

Wavelength dependent $T_{LD50}$ for (A) ALA-induced PpIX mediated PDT, (B) TLD1433 mediated PDT and (C) Ru(II) polypyridine compound 4 by J. Karges et al. [38]. All experiments were performed in HeLa cells (squares) and RPE-1 cells (triangles) (D) $T_{LD50}$ for Ru(II) complexes containing 2,2′-bipyridine, 1,10-phenanthroline, or 2,2′-biquinoline ligands reported by J Zhao et al. [41] were squares, circles, and triangles indicate the three complexes, respectively. Data for A, B, and C were executed in HeLa and RPE-1 cells. Experiments in D are shown for HeLa cells.

Figure 3.

Frequency histogram (Log scale) of calculated $T_{LD50}$ values for all cells compared to A549, HeLa, HL-60, and SK-MEL-28 cells. The data is derived from all Ru PS and treatment conditions listed in Table 2.

Figure 4:

Box and whisker plots of the Log ₁₀(T_LD50) from Ru PS with subcellular co-localization information for cytoplasm, Golgi, Mitochondria, and nuclear accumulation. The x represents the median value and the whiskers 2 standard deviations, indicating a non-gaussian distribution.