Scientists have long wrestled with the inability to penetratecells' membrane walls to deliver drugs, nutrients or biosensors withoutdamaging or destroying the cell. In 2008, researchers at MIT devised a way toaccomplish this using nanoparticles of pure gold, coated with a thin layer of aspecial polymer. With little understanding of how these particles penetratedthe cell wall, the MIT-Swiss team set out to understand why this process worksand the limits on the sizes of particles that can be used.
"In 2008, all we knew is that when we synthesized particles,some would go into the cell and some would not, and we didn't know why," says ReidVan Lehn, a graduate student at MIT and a co-author on the paper. "Themechanism was not understood at all. It was just an observation, essentially.We wanted to be able to understand the design rules associated with bypassingthis membrane so we can develop a new generation of therapeutics that can enterthe cell."
The international team did so using a combination of labexperiments and computer simulations. First, the team demonstrated that thecrucial first step in the process is for coated gold nanoparticles to fuse withthe lipids that form the cell wall. The scientists also demonstrated an upperlimit on the size of such particles that can penetrate the cell wall—a limitthat depends on the composition of the particle's coating. The coating appliedto the gold particles consisted of a mix of hydrophobic and hydrophiliccomponents that form a monolayer—a layer just one molecule thick—on theparticle's surface.
Any of several different compounds can be used, according tothe researchers. Since the nanoparticles themselves are completely coated, thefact that they are made of gold doesn't have any direct effect, except thatgold nanoparticles are an easily prepared model system. However, there is someevidence that the gold particles have therapeutic properties, which could be aside benefit, according to the team. In addition, the researchers observed thatthe mechanism which allows the nanoparticles to pass through the membrane alsoseems to seal the opening as soon as the particle has passed.
"They would go through without allowing even small moleculesto leak through behind them," Van Lehn says.
There are many potential drug development applications thatcould arise from these findings, says Van Lehn. First, because gold particlesare good at capturing X-rays, they could be made to penetrate cancer cells anddestroy them from within.
"Our major goal is working toward the idea of minimalizingthe harmful side effects of chemotherapy," says Van Lehn.
If the coatings can be targeted to a particular cell typethat is the target of a drug, that could also give drug developers asignificant leg up in first-in-class drug development. Another potentialapplication could be in attaching or inserting biosensing molecules on or intocertain cells, enabling scientists to detect or monitor specific biochemicalmarkers such as proteins that indicate the onset or decline of a disease or ametabolic process.
"If we can combine our mechanism with one targeting specificcells, that would be the holy grail of drug development," Van Lehn notes. "Wethink there is a lot of potential here, and we are actively looking to followthat up."
The paper, "Effect of Particle Diameter and SurfaceComposition on the Spontaneous Fusion of Monolayer-Protected Gold Nanoparticleswith Lipid Bilayers," was published online Aug. 5 in Nano Letters, an AmericanChemical Society publication. Other authors on the paper include graduatestudents Prabhani Atukorale, Yu-Sang Yang and Randy Carney, and professorsAlfredo Alexander-Katz, Darrell Irvine and Francesco Stellacci.
