Web Date: May 9, 2012
Turning On Ruthenium To Kill Cancer Cells
A widely used cancer drug, cisplatin damages DNA and kills cells. But it also causes debilitating side effects. Researchers have now developed ruthenium complexes whose cell-killing activity they can switch on at will: The complexes are nontoxic in the dark, but when activated with light, are more toxic to cultured cancer cells than cisplatin (J. Am. Chem. Soc., DOI: 10.1021/ja3009677).
Cisplatin kills cells by crosslinking their DNA and disrupting replication and transcription. Its crosslinking ability doesn’t discriminate between healthy cells and those within tumors. “Sometimes it seems like these treatments are as bad as or worse than the disease,” says Edith Glazer of the University of Kentucky. She and her colleagues thought they could build a more specific metal complex by designing a prodrug—a complex that is nontoxic until activated by an external stimulus.
Researchers have long studied light-activated drugs in a field known as photodynamic therapy. Building on others’ work in the field, Glazer and her colleagues focused on octahedral ruthenium complexes, which are inert in the dark but tend to lose a ligand quickly when illuminated. Although inorganic chemists try to prevent this dissociative decay for some applications, Glazer realized that her team could use the property in their prodrug design. She envisioned the molecule losing a ligand, allowing the complex to then react with DNA like cisplatin does and kill cancer cells.
The researchers synthesized octahedral ruthenium complexes, each with three ligands. One of these ligands included groups that added strain to the complex. When the complexes were exposed to blue-green light, each quickly ejected a ligand and became reactive toward DNA. The researchers then reacted the light-activated Ru complexes with DNA and compared their activity with that of cisplatin; all of these compounds crosslinked DNA, as shown in gel assays.
Then they tested these complexes with lung cancer and leukemia cells in a culture dish and with lung cancer spheroids, clusters of cells 600 µm in diameter that mimic the three-dimensional structure of tumors. The two Ru complexes were up to 200 times as toxic in light as in the dark; after activation with light, they were up to three times as potent against tumor cells as cisplatin.
Questions remain, says Peter Sadler of England’s University of Warwick, about the toxicity and activity of these compounds in animals and people. Glazer plans to collaborate with other researchers to test these compounds and others in animal experiments. Glazer and her colleagues are also tweaking the ruthenium complexes so that red and near-infrared light, which can penetrate tissue, turn them on.
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