Nanoparticle Boosts Chemo Effectiveness

NEW YORK (Reuters Health) - By attaching a chemotherapy drug to a microscopic "nanoparticle," scientists have increased the cancer-killing capacity of the drug while reducing its toxic side effects, experiments in mice show.

Dr. James R. Baker Jr. of the University of Michigan Health System in Ann Arbor and his team attached methotrexate to a multi-branched synthetic macromolecule called a dendrimer. To target it to cancer cells they also attached folic acid to the nanoparticle, along with imaging agents so they could see what went on.

They found that cells that overexpressed folate receptors on their surface readily took up the engineered particle.

"The real advance here is that you can take these particles and inject them into the blood, and they're small enough that they get through the vascular pores and they're actually taken into the cancer cells, which is something that's unique in targeted therapies so far," Baker told Reuters Health.

The folate receptor is overexpressed in a number of human cancers, he and his colleagues note in the journal Cancer Research. Several attempts have been made to attach folic acid to small molecules in order to target therapy, but these constructs haven't bound well to cancer cells.

"They may bind to cells in a tissue culture or test tube, (but) they won't do it in a more active environment like in the body," Baker explained.

The nanoparticle used in his latest work can carry several molecules of folic acid, he explained. "When you put more than one on there it acts like Velcro."

Baker's team implanted mice with KB tumors, which overexpress folate receptors. Four days after implantation, the mice began receiving twice-weekly injections with targeted nanoparticles, non-targeted nanoparticles, methotrexate alone, or saline solution.

None of the animals injected with the nanoparticles showed any toxicity up to 99 days after the experiment began.

Treatment with methotrexate alone shrank tumors but produced severe toxicity, as evidenced by the animals' loss of body weight, which became lethal within 36 days.

Methotrexate delivered via nanoparticles was effective at doses 10-fold lower compared with that needed for methotrexate alone, the researchers found. "The real key is that we haven't even gotten to dose-limiting toxicity," Baker said.

He and his colleagues are now planning additional studies to identify the dose at which the targeted therapy becomes toxic. Phase I trials in humans could begin within 18 months, Baker added.

SOURCE: Cancer Research, June 15, 2005.