RE:RE:RE:RE:RE:RE:RE:RE:RE:publication from Dr McFarland's team - Dec 9Without paying for the full text of the new paper one can still glean quite a bit from the supporting information provided along with the abstract:
This study introduces two new ruthenium compounds. To test them, the researchers cultivated samples of
breast cancer,
NSCLC and
2 kinds of melanoma cell lines. Each cell line was divided into two separate well plates with different oxygen culture conditions created -
normoxic (18.5% - 21% O2) and
hypoxic (1% O2). After 4-6 hours of incubation under these oxygen conditions both plates were treated with the compound and allowed to incubate overnight for an additional 16 hours. Before being treated with light, dark toxicity was determined. They were then irradiated with
white, blue, green and red light. The plates were then allowed to incubate overnight for 20 hours. The light induced potency for each cell line under each set of conditions was then determined and a phototherapeutic index value assigned. A phototherapeutic index is the ratio of dark to light EC50 values ( EC50 value = "potency" - the lower the EC50, the less the concentration of a drug is required to produce 50% of maximum effect)
The results are in the Abstract - "the compound...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."
As CancerSlayer pointed out below, as recently as Aug. 2020 the highest PI achieved in hypoxia was (what was considered then) "
an unprecedented PI > 90" in white and green light in a new Osmium PS..
No wonder Dr. McFarland and team have christened this new compound a "Light-Triggered
Ruthenium Ubertoxin" and deemed the potency in extreme hypoxia
inexplicable!
CancerSlayer wrote:
Hi Yajne....the following are the 2020 results for Osmium:
Note: The phototherapeutic index (PI) for Osmium in 1% O2 hypoxia conditions was significantly lower for Osmium (PI > 90) compared to this more recent compound (PI > 5800). As far as I can tell, the Osmium treatment (in mice) also required significantly higher concentrations to be active. It looks like this newest/latest compound has raised the bar even higher & can now claim...."the largest values reported to date for any compound class."
Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy†
First published on 3rd August 2020
Abstract
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. This paper reports the first metal-based photosensitizer that approaches the ideal properties for a phototherapy agent. The Os(phen)2-based scaffold was combined with a series of IP-nT ligands, where phen = 1,10-phenanthroline and IP-nT = imidazo[4,5-f][1,10]phenanthroline tethered to n = 0–4 thiophene rings. Os-4T (n = 4) emerged as the most promising complex in the series, with picomolar activity and a phototherapeutic index (PI) exceeding 106 in normoxia. The photosensitizer exhibited an unprecedented PI > 90 (EC50 = 0.651 μM) in hypoxia (1% O2) with visible and green light, and a PI > 70 with red light. Os-4T was also active with 733 nm near-infrared light (EC50 = 0.803 μM, PI = 77) under normoxia. Both computation and spectroscopic studies confirmed a switch in the nature of the lowest-lying triplet excited state from triplet metal-to-ligand charge transfer (3MLCT) to intraligand charge transfer (3ILCT) at n = 3, with a lower energy and longer lifetime for n = 4. All compounds in the series were relatively nontoxic in the dark but became increasingly phototoxic with additional thiophenes. These normoxic and hypoxic activities are the largest reported to date, demonstrating the utility of osmium for phototherapy applications. Moreover, Os-4T had a maximum tolerated dose (MTD) in mice that was >200 mg kg−1, which positions this photosensitizer as an excellent candidate for in vivo applications.