Anticancer Agent with Inexplicable Potency in Extreme Hypoxia: Characterizing a Light-Triggered Ruthenium Ubertoxin

Abstract

Tumor hypoxia renders treatments ineffective that are directly (e.g., radiotherapy and photodynamic therapy) or indirectly (e.g., chemotherapy) dependent on tumor oxygenation. This study introduces a ruthenium compound as a light-responsive anticancer agent that is water-soluble, has minimal dark cytotoxicity, is active at concentrations as low as 170 pM in ∼18.5% O2 normoxia and near 10 nM in 1% O2 hypoxia, and exhibits phototherapeutic indices as large as >500,000 in normoxia and >5,800 in 1% O2 hypoxia using broadband visible and monochromatic blue light treatments. These are the largest values reported to date for any compound class. We highlight the response in four different cell lines to improve rigor and reproducibility in the identification of promising clinical candidates.

Intraligand Excited States Turn a Ruthenium Oligothiophene Complex into a Light-Triggered Ubertoxin with Anticancer Effects in Extreme Hypoxia

“…The quantum yields of Ru-3T and Ru-4T still fall short of those for the analogous complexes with nonmethylated phen ancillary ligands (Φ Δ = 0.88 and 0.87, unpublished results), suggesting that these complexes with strain-inducing ligands have competing pathways for excited-state relaxation that include ligand loss via the 3 MC state. The 1 O 2 quantum yields for the strained bis(6,6′-dmb) analogs of Ru-2T, Ru-3T, and Ru-4T were previously determined to be 0.09 a , 0.42, and 0.43, respectively, 78,88 also confirming the abrupt switch in photophysical behavior between n = 2 and 3 for related but structurally different ancillary ligands and highlighting the impact of the ancillary ligand identity on the overall properties such as 1 O 2 sensitization and ligand dissociation. We have addressed this relationship in more detail elsewhere.…”

“…Inspired by previous examples of dual-action PDT/PCT agents, 45,52,54,64,88 we have shown that complexes of the type [Ru(6,6′-dmb) 2 (IP-nT)] 2+ (n = 3, 4 thiophenes; IP = 1Himidazo [4,5-f ] [1,10]phenanthroline) undergo photoinduced ligand loss, leading to substitution of the strain-inducing 6,6′dmb ligand for solvent molecules, while maintaining moderately high 1 O 2 quantum yields (Φ Δ ) of 42−43% for the intact complex. 78,88 Because the [Ru(6,6′-dmb) 2 (IP-4T)] 2+ complex was substantially more photocytotoxic in normoxia relative to its IP-3T counterpart (PI = 3400−3800 vs 400− 600), it was investigated more rigorously (four cell lines, normoxia, and 1% hypoxia) alongside its close relative [Ru(2,9-dmp) 2 (IP-4T)] 2+ (where 2,9-dmp = 2,9-dimethyl-1,10-phenanthroline, compound Ru-4T in Chart 1), also with strain-inducing polypyridyl ligands substituted with methyl groups. From this comparative study using four different cancer cell lines, several surprising findings emerged.…”

“…From this comparative study using four different cancer cell lines, several surprising findings emerged. 78 First, the identity of the coligand made a marked difference in the photoactivity of the complexes, with 2,9-dmp in the case of Ru-4T being superior to 6,6′-dmb in [Ru(6,6′-dmb) 2 (IP-4T)]Cl 2 . Second, [Ru(6,6′-dmb) 2 (IP-4T)]Cl 2 was completely inactive in 1% hypoxia in most of the cell lines despite undergoing photoinduced ligand loss in deoxygenated, cell-free solutions.…”

BODIPY-Based Photothermal Agents for Cancer Treatment

“…SAR determination experiments demonstrate the light-to-heat generation abilities of these compounds, especially of 1b which shows particularly high SAR values with low concentrations. The agents are also over 830ʹ000 times more toxic after light activation combined with a photothermal and oxygen-independent MOA (PI of over 360ʹ000 under hypoxic condition of 0.2% O2), to the best of our knowledge the highest values reported so far (compare with [69] ). In short, these compounds show high potential for overcoming the existing drawbacks of PDT and PTT.…”

Synthesis and Coordination Chemistry of a Benzannulated Bipyridine: 6,6′-Biphenanthridine

“…The UV−vis signatures of the photoproduct generated from both complexes show clear indication of liberated 6,6′-biphenanthridine, similar to what has been reported for heteroleptic, lighttriggered ruthenium ubertoxins containing two bipyridine and one π-extended bipyridine-based quaterthiophene ligand. 59 Upon ligation to Ru(II), a series of broad, lower energy absorptions become visible with λ max = 549 nm (4700 M −1 cm −1 ) for the lowest-energy band of [Ru(biphe) 3 ]Cl 2 , and λ max = 530 nm (2300 M −1 cm −1 ) the corresponding values for [Ru(bpy) 2 (biphe)](BPh 4 ) 2 (Figure 7a). TDDFT calculations (Figures S14 and S15, Tables S6 and S7) on the gas-phase optimized ground-state structures of both dications point toward the expected metal-to-ligand charge-transfer (MLCT) character to the lowest-energy absorption band, as the HOMO through HOMO − 2 have metal t 2g -type character, while the LUMO through LUMO + 2 are largely ligand-based (Tables S3 and S4).…”