Conventional chemotherapeutic agents play a significant role in today's cancer treatment which include platinum-based cytotoxic agents that attack cancer cells and kill them. However, they even damage healthy living cells and cause side-effects. A new approach has been identified by the ETH Zurich researchers with drugs of this kind that selectively kill cancer cells leaving healthy cells unaffected.
Platinum can be cytotoxic when oxidized to platinum(II) and occurs in this form in conventional platinum-based chemotherapeutics. Non-oxidized platinum(0), however, is far less toxic to cells. Based on this knowledge, a team led by Helma Wennemers, Professor at the Laboratory of Organic Chemistry, and Michal Shoshan, a postdoc in her group, looked for a way to introduce platinum(0) into the target cells, and only then for it to be oxidized to platinum(II). To this end, they used non-oxidized platinum nanoparticles, which first had to be stabilized with a peptide. They screened a library containing thousands of peptides to identify a peptide suitable for producing platinum nanoparticles (2.5 nanometers in diameter) that are stable for years.
‘The new approach will lead to the development of drugs with improved selectivity for certain types of cancer.’
Oxidized inside the cell
Tests with cancer cell cultures revealed that the platinum(0) nanoparticles penetrate into cells. Once inside the specific environment of liver cancer cells, they become oxidized, triggering the cytotoxic effect of platinum(II).
Studies with ten different types of human cells also showed that the toxicity of the peptide-coated nanoparticles was highly selective to liver cancer cells. They have the same toxic effect as Sorafenib, the most common drug used to treat primary liver tumors today. However, the nanoparticles are more selective than Sorafenib and significantly more so than the well-known chemotherapeutic Cisplatin. It is therefore conceivable that the nanoparticles will have fewer side effects than conventional medication.
Joining forces with ETH Professor Detlef Günther and his research group, Wennemers and her team were able to determine the platinum content inside the cells and their nuclei using special mass spectrometry. They concluded that the platinum content in the nuclei of liver cancer cells was significantly higher than, for instance, in colorectal cancer cells. The authors believe that the platinum(II) ions - produced by oxidation of the platinum nanoparticles in the liver cancer cells - enter the nucleus, and there release their toxicity.
"We are still a very long and uncertain way away from a new drug, but the research introduced a new approach to improve the selectivity of drugs for certain types of cancer - by using a selective activation process specific to a given cell type," Wennemers says. Future research will expand the chemical properties of the nanoparticles to allow for greater control over their biological effects.