Previous studies in cell cultures have suggested that attaching anticancer drugs to nanoparticles for targeted delivery to tumour cells could increase the therapeutic response. Now, researchers at the University of Michigan in the US have shown that this nanotechnology-based treatment is effective in living animals.
The next step is to work out the maximum therapeutic dose of the treatment in research animals, with the aim of starting human trials within two years.
"This is the first study to demonstrate a nanoparticle-targeted drug actually leaving the bloodstream, being concentrated in cancer cells, and having a biological effect on the animal's tumour," said James Baker, professor of biologic nanotechnology at U-M, who headed the study.
Baker, who also directs the Michigan Nanotechnology Institute for Medicine and the Biological Sciences, said the technique could improve the therapeutic index of cancer drugs, raising efficacy and reducing toxicity, and 'turn cancer into a chronic, manageable disease'.
The drug delivery vehicle used by U-M scientists is a manmade polymer molecule called a dendrimer. Less than five nanometers in diameter, these dendrimers are small enough to slip through tiny openings in cell membranes. Dendrimers have a tree-like structure with many branches where scientists can attach a variety of molecules, including drugs.
In experiments reported in the journal Cancer Research (15 June), the U-M scientists attached the widely-used anticancer drug methotrexate to branches of the dendrimer. On other branches, they attached fluorescent imaging agents and folic acid or folate, a vitamin that cancer cells need in huge amounts.
To soak up as much folate as possible, some cancer cells display more docking sites called folate receptors on their cell membranes. By taking advantage of a cancer cell's appetite for folate, U-M scientists are able to prevent the cells from developing resistance to chemotherapeutic drugs.
"It's like a Trojan horse," explained Baker. "Folate molecules on the nanoparticle bind to receptors on tumour cell membranes and the cell immediately internalises it, because it thinks it's getting the vitamin it needs. But while it's bringing folate across the cell membrane, the cell also draws in the methotrexate that will poison it."
In conventional chemotherapy, drugs like methotrexate must diffuse across a cell membrane to get inside cancer cells, according to Baker. This is a slow process and requires a high concentration of drug in the extra-cellular fluid, which can damage normal cells and tissues.
When tested in laboratory mice that had received injections of human epithelial cancer cells, the nanoparticle-based therapy using folic acid and methotrexate was 10 times more effective at delaying tumour growth than the drug given alone. Nanoparticle treatment also proved to be far less toxic to mice in the study than the anticancer drug alone.
In the team's longest trial, which lasted 99 days, 30 to 40 per cent of the mice given the nanoparticle with methotrexate survived, while all the mice receiving free methotrexate died - either from overgrowth of the tumour or from toxic effects of the drug.
The fluorescent tags on the dendrimers also allowed the researchers to demonstate that the dendrimers entered into cancer tissue and were quickly filtered from the blood and eliminated in urine, with no evidence that they went int other tissues such as the brain. The nanoparticles also did not appear to generate an immune response in mice in the study.
The team is also planning to explore the use of nanotechnology-based therapies using other chemotherapeutic drugs.
U-M has filed a patent application on targeted nanoparticle technology, and a licensing agreement is currently being negotiated with Avidimer Therapeutics, a biopharmaceutical company in which Baker holds a significant financial interest.