Taking Aim With Nanoparticle PEBBLEs

First developed as sensors to explore and monitor cellular processes, PEBBLEs now hold promise for diagnosing and treating cancer, said Raoul Kopelman, who is the Kasimir Fajans Collegiate Professor of Chemistry, Physics and Applied Physics at U-M. At the 229th national meeting of the American Chemical Society in San Diego, Calif., March 17, Kopelman will describe the research that he and his collaborators have been doing over the past seven years, including encouraging preliminary results using PEBBLEs to treat a virulent form of brain cancer in rats.

PEBBLEs are polymer spheres, typically 20 to 200 nanometers in diameter—about the size of a virus. The spheres carry an assortment of molecules on their surfaces, some to guide the PEBBLEs to their targets inside the body, some to enhance their visibility on MRI images, and others to deliver a deadly cargo to cancer cells when triggered by exposure to light.

Unlike chemotherapy drugs that attack tumors by invading cancer cells and disrupting their DNA, PEBBLEs never enter the cells they target. Instead, they attach to the outside of the targeted cell and shoot reactive oxygen species into it, setting off "an avalanche of damage," said Kopelman. By staying outside the cell, PEBBLEs avoid a problem that thwarts many chemotherapy drugs.

"The really bad cancer cells get immune to chemotherapy drugs – they pump the drugs back out," Kopelman said. Cancer cells can't do that to PEBBLEs, though, because PEBBLEs are already on the outside. Another advantage: the "killer oxygen" that PEBBLEs deliver to cancer cells is too unstable to wander off and damage healthy cells, so only targeted cells are affected. Including molecules that make PEBBLEs more visible in MRI images provides an added bonus, helping to show where tumors are located and how they respond to treatment.

In recent experiments with a small number of rats that had a type of brain cancer called 9L-gliosarcoma, PEBBLE-based treatment significantly increased survival time. People who get that type of cancer usually live less than four months without treatment; rats die within about five days. When Kopelman's group treated rats with PEBBLEs that weren't even tailored to home in on cancer cells, the rats lived twice as long. With targeted PEBBLEs, some rats were still alive and active two months later, and MRI images showed that their tumors had vanished.

Kopelman and coworkers plan to tinker with the PEBBLEs a bit more before trying them on larger numbers of rats, and PEBBLE-based cancer treatments for people are a long way off. But "there's no doubt," said Kopelman, "that nanoparticles such as PEBBLEs can do a fantastic job for therapy, diagnostics and a combination of the two."

Kopelman's collaborators on the work he will discuss in San Diego are Martin Philbert, professor of toxicology and Associate Dean for Research in the School of Public Health; Brian Ross, a professor of biological chemistry and of radiology in the Medical School; Alnawaz Rehemtulla, an associate professor of environmental health sciences, radiation oncology and radiology with joint appointments in the Medical School and the School of Public Health; and Yong-Eun Lee Koo, a research associate in the chemistry department, College of Literature, Science and the Arts.

To date, the researchers have received $11.5 million from the National Cancer Institute for their work with PEBBLEs.

Related links:

* Raoul Kopelman (http://ipumich.temppublish.com/public/experts/ExpDisplay.php?beginswith=Kopelman&SubmitButton=Search)

* Kopelman laboratory (http://www.umich.edu/%7Ekoplab/)

* Fighting Cancer, Cell by Cell (http://lifesciences.umich.edu/research/featured/cancer.html)

* American Chemical Society (http://www.chemistry.org/)