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Single-Shot Chemo

Nanospheres that target cancer cells and gradually release drugs could make treatment safer and more effective.
April 12, 2006

A single treatment of drug-bearing nanoparticles effectively destroys prostate cancer tumors in mice, according to experiments by researchers at MIT and Harvard Medical School. This approach could lead to powerful treatments without the side effects associated with cancer therapy, say the scientists.

“We did a single injection of the particles, and then followed the tumor for the next 109 days, and showed that we basically had complete tumor elimination,” says Omid Farokhzad, assistant professor of anesthesia at Harvard Medical School, who, along with Robert Langer, chemical engineering professor at MIT, led the research. Because the ingredients used to make the nanoparticle drug system have already been okayed by the FDA for other purposes, the researchers hope to win quick approval for testing the new technology in humans. The results were published this week in the Proceedings of the National Academy of Sciences.

[For an image of cells with embedded nanoparticles, click here.] 

Because many patients receive regular screenings for prostate cancer, doctors increasingly discover and treat the disease at an early stage, when it is still confined to single tumors. At this stage, a single injection of radioactive materials directly into the tumor can be an effective treatment, killing the tumor over several months. But this treatment has side effects, such as erectile dysfunction, in about 40 percent of patients, says Farokhzad. Surgery, another option, has risks of complications. For later-stage cancer, chemotherapy is an option, but that also comes with side effects – and requires many doses.

The researchers believe the nanoparticles should provide the one-shot therapy advantage of radiation, but without the side effects, in part because the particles deliver drugs specifically to the inside of cancer cells, avoiding damage to healthy tissue.

To make the nanoparticles, the researchers mix together a prostate cancer drug (docetaxel) and polymers that are already FDA-approved (one of them is used for sutures). The polymer formed spheres with the drugs trapped within. The researchers then chemically attach pieces of RNA, called aptamers, to the surface of the spheres. The RNA folds into shapes that fit into complementary structures on the surface of prostate-cancer cells.

In the mouse experiments, researchers allowed tumors to grow to a certain size before injecting the targeted nanoparticles, or one of a variety of control substances, directly into the tumor. In controls using either saline, polymer nanoparticles without the drug, or the drug alone, almost all the mice died during the experiment. In contrast, all of the mice injected with the targeted nanoparticles survived, and in most cases (five out of seven) the tumors disappeared.

A key to the nanoparticles’ effectiveness is the ability of their RNA strands to bind to a cancer cell membrane. The cell then pulls the particles inside. Having the particles inside the cell has two advantages: it gets the drug where it needs to be to kill the cells, and it decreases the concentration of the drug outside the cancer cells, thereby decreasing toxicity to healthy tissue. The fact that the polymer releases the drug gradually also helps – the drug is released over the hours or days it takes for the particles to be pulled into cells, where it continues to be released, killing the cells.

In contrast, when the drug is injected into the tumor without being encapsulated inside particles, it has little effect, and the tumor continues growing. Apparently, the drug diffuses out of the tumor area before it can kill off all the cancer cells.

Early toxicity trials of the nanoparticles could begin in two years, if further animal studies go well, says Farokhzad.

The drug-delivery technology is part of a larger effort by researchers to use nanotechnology to revolutionize cancer treatment. Joseph DeSimone, chemistry and chemical engineering professor at the University of North Carolina at Chapel Hill and North Carolina State University, for example, has recently started mouse trials using his own polymer-based nanoparticles for drug deliver. University of Michigan physician James Baker’s nanoparticles based on highly branched structures called dendrimers have also shown success against cancer in rodents.

The MIT-Harvard researchers are also working on targeting pancreatic cancer and eventually breast cancer and cardiovascular disease. Henry Brem, neurosurgeon and director of the department of neurosurgery at Johns Hopkins University School of Medicine, would like to adapt the nanoparticles for brain cancer, especially for treating tumors difficult to reach with surgery. “It’s not going to affect the brain, it will only affect the tumor cells. To just inject it into the tumors and eradicate them, that would be a huge step forward for neural oncology. If we could get a hold of it, we would do it tomorrow, in the laboratory,” he says.

Eventually, the MIT-Harvard researchers hope to design nanoparticles that can be injected into the bloodstream, from which they could seek out cancer cells anywhere in the body, making it possible to treat late-stage metastasized cancer. “Even though this represents a small percentage of patients that actually have the disease, these are the ones that have no therapeutic option available to them,” Farokhzad says. “So the idea of having nanoparticles that can circulate through the body, find cancer cells, and kill them, is very, very attractive.”

To this end, they are generating “libraries” of nanoparticles of various sizes with different chemical properties and molecular attachments, which they will test in vitro and in vivo to identify those that are most effective at finding and destroying cancer cells without becoming lodged in healthy organs.

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