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.