Hypoxia presents a two-fold challenge in the treatment of cancer, as low oxygen conditions induce biological changes that make malignant tissues simultaneously more aggressive and less susceptible to standard chemotherapy....

A series of strained Ru(II) complexes were studied for potential anticancer activity in hypoxic tissues. The complexes were constructed with methylated ligands that were photolabile and an imidizo[4,5‐f][1,10]phenanthroline ligand that contained an appended aromatic group to potentially allow for contributions of ligand‐centered excited states. A systematic variation of the size and energy of the aromatic group was performed using systems containing 1–4 fused rings, and the photochemical and photobiological behaviors of all complexes were assessed. The structure and nature of the aromatic group had a subtle impact on photochemistry, altering environmental sensitivity, and had a significant impact on cellular cytotoxicity and photobiology. Up to 5‐fold differences in cytotoxicity were observed in the absence of light activation; this rose to 50‐fold differences upon exposure to 453 nm light. Most significantly, one complex retained activity under conditions with 1% O2, which is used to induce hypoxic changes. This system exhibited a photocytotoxicity index (PI) of 15, which is in marked contrast to most other Ru(II) complexes, including those designed for O2‐independent mechanisms of action.

Ru­(II) complexes that undergo photosubstitution reactions from triplet metal-centered (3MC) excited states are of interest in photochemotherapy (PCT) due to their potential to produce cytotoxic effects in hypoxia. Dual-action systems that incorporate this stoichiometric mode to complement the oxygen-dependent photosensitization pathways that define photodynamic therapy (PDT) are poised to maintain antitumor activity regardless of the oxygenation status. Herein, we examine the way in which these two pathways influence photocytotoxicity in normoxia and in hypoxia using the [Ru­(dmp)2(IP-nT)]2+ series (where dmp = 2,9-dimethyl-1,10-phenanthroline and IP-nT = imidazo­[4,5-f]­[1,10]­phenanthroline tethered to n = 0–4 thiophene rings) to switch the dominant excited state from the metal-based 3MC state in the case of Ru-phen–Ru-1T to the ligand-based 3ILCT state for Ru-3T and Ru-4T. Ru-phen–Ru-1T, having dominant 3MC states and the largest photosubstitution quantum yields, are inactive in both normoxia and hypoxia. Ru-3T and Ru-4T, with dominant 3IL/3ILCT states and long triplet lifetimes (τTA = 20–25 μs), have the poorest photosubstitution quantum yields, yet are extremely active. In the best instances, Ru-4T exhibit attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar in hypoxia, with phototherapeutic index values in normoxia of 105–1012 and 103–106 in hypoxia. While maximizing excited-state deactivation through photodissociative 3MC states did not result in bonafide dual-action PDT/PCT agents, the study has produced the most potent photosensitizer we know of to date. The extraordinary photosensitizing capacity of Ru-3T and Ru-4T may stem from a combination of very efficient 1O2 production and possibly complementary type I pathways via 3ILCT excited states.

Hypoxia presents a challenge to anticancer therapy, reducing the efficacy of many available treatments. Photodynamic therapy is particularly susceptible to hypoxia, given that its mechanism relies on oxygen. Herein, we introduce two new osmium-based polypyridyl photosensitizers that are active in hypoxia. The lead compounds emerged from a systematic study of two Os­(II) polypyridyl families derived from 2,2′-bipyridine (bpy) or 4,4′-dimethyl-2,2′-bipyridine (dmb) as coligands combined with imidazo­[4,5-f]­[1,10]­phenanthroline ligands tethered to n = 0–4 thiophenes (IP-nT). The compounds were characterized and investigated for their spectroscopic and (photo)­biological activities. The two hypoxia-active Os­(II) photosensitizers had n = 4 thiophenes, with the bpy analogue 1-4T being the most potent. In normoxia, 1-4T had low nanomolar activity (half-maximal effective concentration (EC50) = 1–13 nM) with phototherapeutic indices (PI) ranging from 5500 to 55 000 with red and visible light, respectively. A sub-micromolar potency was maintained even in hypoxia (1% O2), with light EC50 and PI values of 732–812 nM and 68–76, respectively currently among the largest PIs for hypoxic photoactivity. This high degree of activity coincided with a low-energy, long-lived (0.98–3.6 μs) mixed-character intraligand charge-transfer (3ILCT)/ligand-to-ligand charge-transfer (3LLCT) state only accessible in quaterthiophene complexes 1-4T and 2-4T. The coligand identity strongly influenced the photophysical and photobiological results in this study, whereby the bpy coligand led to longer lifetimes (3.6 μs) and more potent photo-cytotoxicity relative to those of dmb. The unactivated compounds were relatively nontoxic both in vitro and in vivo. The maximum tolerated dose for 1-4T and 2-4T in mice was greater than or equal to 200 mg kg–1, an excellent starting point for future in vivo validation.