"We believe that wormlike particles will be a challenge for macrophages to engulf and clear,” DeSimone says, “because such filamentous objects are known to be difficult for macrophages to reel in. Particles that are more spherically symmetric can be engulfed in one fell swoop by macrophages, but that is more difficult for such filamentous particles."
The findings of DeSimone and his team are a surprising but welcome development in the use of nanotechnology for drug delivery, says Christian Melander, an assistant professor of organic chemistry at North Carolina State University in Raleigh, who has been studying the use of gold nanoparticles as a means of assisting the delivery of an HIV (human immunodeficiency virus) treatment that is under development as well as to help that drug to latch onto receptors (protein molecules embedded in a cell's membrane) on the outside of T cells to shield them from HIV.
Although Melander and his colleagues at N.C. State and the University of Colorado at Boulder work with an inorganic substance (gold) and cannot alter the shape of the particles they work with, Melander says that DeSimone's work "shows insight into particle delivery that most people wouldn't have predicted. It also shows there's a lot more fundamental research in this area that must be done." Melander's team, which is not involved in any of DeSimone's work, is currently testing their gold nanoparticles' ability to cross through a simulation of the blood–brain barrier that prevents many substances from passing into the brain from the bloodstream.
To help get their technology into drug companies' hands more quickly, DeSimone and his colleagues have built a device that make different-shaped nanoparticles in bulk using molds that pop out these particles like so many ice cubes. The Particle Replication in Nonwetting Templates (PRINT) technology helped earn DeSimone this year's $500,000 Lemelson–M.I.T. Prize in June. "We use lithography to make one wafer that will be the master template (for the nanoparticles)," he says. "From there, we're able to make thousands of linear feet of molds."
DeSimone and his colleagues have been able to make these mini molds since 2005, and published a paper in the Journal of the American Chemical Society at the time describing their work. Those molds were only 0.04 inch (one millimeter) square and yielded very few nanoparticles of controlled size and shape. However, "we can now make many square meters of molds in a cost-effective manner that allows us to make hundreds of milligrams of nanoparticles of a variety of shapes and sizes that allow us to probe biological systems," DeSimone says.
The next step is for Liquidia Technologies, the North Carolina–based company DeSimone co-founded in 2004 with a group of U.N.C. researchers, to refine the printing methods and scale up production. Liquidia has built a machine that yields tens of grams of nanoparticles in a single day, and the company hopes to be able to produce multiple kilograms of nanoparticles daily. He is hoping to have U.S. Food and Drug Administration–approved equipment in place by the middle of 2009 to produce these nanoparticles and move into clinical trials shortly thereafter. First on DeSimone's list to study are siRNA (short interfering RNA) molecules that may be able to keep cancer cells from producing the proteins that make them dangerous as well as the cancer drugs docetaxel, cisplatin and doxorubicin.