A new class of specially engineered nanoparticles that can target, image, and kill tumor cells could be a potent weapon against cancer. The new nanoengineered system, designed by physician and researcher James Baker and his colleagues at the University of Michigan, contains gold nanoparticles with branching polymers called dendrimers that sprout off the nanoparticle's surface.
The particles could be used to launch a multiprong attack against tumors. The dendrimer arms can carry a number of different molecules, including molecules that target cancer cells, fluorescent imaging agents, and drugs that slow down or kill the cells. Once enough of the nanoparticles have gathered inside cancer cells, researchers could kill the tumors by using lasers or infrared light to heat up the gold nestled inside the dendrimers. The nanoparticles could thus kill tumors "by combining chemical therapy and physical therapy," says University of Michigan researcher Xiangyang Shi, who was involved in the work.
In a paper published in the July issue of Small, the researchers demonstrated targeting and imaging cancer cells in a laboratory dish with the new gold-dendrimer hybrid nanoparticles. They hooked four or five folic-acid and fluorescent-dye molecules to each of the dendrimer branches. Then they processed the particles to remove any extra surface charge, which can make the otherwise safe polymers toxic.
Cancer cells have many more folic-acid receptors on their surface than healthy cells do. The folic acid-laden nanoparticles attached to human cancer cells, and the cells swallowed them, along with the folic acid. The particles, which are only three nanometers wide, easily passed through the cell membrane.
Using a microscope, the researchers could see the particles that had accumulated inside the cells because of the dye molecules. The gold in the particle enhanced the contrast enough for the researchers to see that the particles gathered inside the cells in tiny spherical structures called lysosomes. The goal, Baker says, is to make particles that target cancer genes inside cells. "You would bind this material to, let's say, an oncogene in a cell and knock out the oncogene without harming anything else," he says.
But first, the researchers will have to show that their material works inside animals. Many other research groups have developed multifunctional nanoparticles to seek out cancer cells and deliver imaging molecules and drugs. Hundreds of different materials are now undergoing tests--gold nanoparticles, silica nanoparticles, polymer shells, and gold-coated glass beads, to name a few. To work in humans, any cancer nanotherapy has to pass three major challenges: the nanoparticles should target only cancer cells; any nanoparticles that do not accumulate inside cells should get eliminated from the body; and the particles should not trigger the body's immune response.
The first goal--targeting tumors--has not been easy. "Specificity in drug delivery has been historically a very elusive goal," says Mauro Ferrari, chair of the biomedical-engineering department at the University of Texas Health Science Center, in Houston. Because the new particles have dendrimers on which the researchers can attach different targeting molecules, the technique might work. But the real test will be doing that inside the body. "Targeting cancer cells can be done in a million different ways in the lab," Ferrari says. "But translating the technique into animals and humans has proven to be very difficult."
Baker believes that the polymer dendrimers should do the trick. In a 2005 study, his research team showed that dendrimer molecules--without gold inside--that were loaded with folic acid and a cancer drug specifically targeted human tumors in mice, and slowed or killed the tumors more efficiently than the drug alone. The researchers are now testing the new gold-dendrimer hybrid particles in mice and expect the particles to be just as effective as the plain dendrimers.
The small size of the new particles should ensure that they get eliminated from the body. The particles are smaller than most other nanoparticle systems designed for cancer therapy, according to Baker, so they shouldn't accumulate in vital organs such as the kidney, liver, or lungs. But their small size might raise other safety issues. Inside animals or humans, the nanoparticles could get into other cells, says Raoul Kopelman, a professor at the University of Michigan's Center for Biological Nanotechnology, who was not involved in the new work. "If you deal with animals or humans, there are many kinds of cells," Kopelman says. "Will they get into other cells like immune cells? It needs to be tested."
The most important problem to solve, says Ferrari, is how to make nanoparticles that can stealthily avoid the body's natural defense mechanisms and get to tumors. "The body has so many booby traps that keep drugs and nanoparticles and everything that is foreign [from getting] into anything of significance in the body," he says. "If you can build on top of the dendrimer platform the ability to make it across biological barriers with great efficiency, then we have a great breakthrough."