Nanoparticles of a Different Stripe

A new material can break through a cell membrane without killing the cell.

Particles that cross a cell's membrane usually don't get very far. The membrane recognizes them as foreign objects and closes them off in little pockets. But now, scientists at MIT have created coated nanoparticles that can slip inside a cell without triggering its self-protective mechanism. Such materials could offer a more effective way to deliver drugs or imaging agents to the interior of a cell.

Small and striped: Gold nanoparticles coated with alternating stripes of hydrophobic and hydrophilic molecules (illustrated above) can penetrate cells without killing them. Credit: Francesco Stellacci/Nature Materials

The research is part of a broad effort to harness nanotechnology for the diagnosis and treatment of disease--cancer, in particular. Nanoparticles are attractive as drug delivery vehicles because they are small enough to be ingested by cells. Delivering a compound directly to a cancer cell's biochemical machinery could make it more effective and help reduce side effects.

Particles less than a few nanometers in size can enter cells readily, but it's the bigger nanoparticles--in the five- to ten-nanometer range--that have practical advantages. A larger particle has more surface area, so it could potentially carry not only more of a drug but perhaps other compounds, such as imaging agents, at the same time.

Researchers have tried various strategies for getting larger particles past the cell membrane. Some have coated the particles with peptides--short fragments of protein--that allow them to penetrate cells. Other work has focused on synthetic materials that allow the particles to enter the cell through brute force. For example, electrostatically charged particles can open up pores in the cell's membrane and pass through them. "If you generate a pore, that short-circuits the role of ionic channels for a while," says Francesco Stellacci, an associate professor of materials science at MIT. But disrupting ionic channels can be fatal to the cell. "If you generate a pore, the material is inherently cytotoxic," Stellacci says. "The cell dies."

Stellacci and his colleagues incorporated properties of the cell-penetrating peptides into their synthetic material. They coated gold nanoparticles six nanometers in diameter with alternating stripes of hydrophobic and hydrophilic molecules, mimicking the ordered structure of the peptides researchers have tried to use in the past. They then labeled the gold nanoparticles with fluorescent dye and tested them on mouse immune cells. The group found that the nanoparticles entered the cells and distributed themselves throughout the cytosol, the cell's internal fluid, without killing the cell. The researchers published their findings in a recent edition of Nature Materials.

The researchers also found that nanoparticles coated with the same molecules, but in a random pattern, triggered the cell's defenses: the particles were enclosed in small pockets, walled off from the cytosol. "To our surprise, they have these properties only when the mixture is organized in an orderly way," Stellacci says. Why the arrangement seems to make such a big difference remains a mystery.

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Coating nanoparticles with synthetic molecules instead of peptides has some advantages, says Daniel Feldheim, professor of chemistry at the University of Colorado at Boulder. Peptides are generally more expensive and difficult to synthesize, and in his lab, Feldheim has found that peptide-coated particles can clump together or otherwise be unstable under certain conditions.

"I really thought it was a spectacular paper," Feldheim says. "It was such a great example of how nanometer-scale structure and organization can make a huge difference."