Penn scientists use protein fragments to 'fool' the immune system and deliver cancer drugs

One of the hot trends in cancer medicine is using tiny particles to deliver drugs directly to a tumor, rather than bombarding the whole body with chemotherapy. But the immune system treats these nanoparticles as foreign invaders, so it tries to clear them before they can do their job.

The solution, says a team of University of Pennsylvania researchers, is to make the foreign particles seem like natives.

The group reported Thursday it had done just that in lab mice, attaching customized protein fragments to the particles that tricked the animals' immune-system "border guards" into relaxing their vigilance.

The scientists said their technique significantly improved the performance of two kinds of nanoparticles: one laden with tumor-shrinking medicine, the other loaded with dye that can be used to capture images of tumors.

The concept also could prove useful in improving the durability of much larger foreign objects in the body, such as pacemakers and other implants whose plastic parts can degrade over time, said team leader Dennis E. Discher. The results are being published in Friday's issue of the journal Science. Pia L. Rodriguez, who earned her doctorate in December, is the first author.

Though it will be years before this technique is ready for human patients, researchers not involved with the work said it was a promising advance.

"It is remarkably clever," said Samir Mitragotri, a chemical engineering professor at the University of California at Santa Barbara who studies how nanoparticles interact with cells.

The key was fooling the immune-system sentries called macrophages, a type of white blood cell that continually makes contact with objects in the bloodstream to check for the presence of a protein called CD47.

CD47 is a marker of "self" - what Discher likened to a passport that identifies a cell as native to the body.

If the object in question, such as a red blood cell, has CD47 on its membrane, then the macrophage lets go.

If the object does not contain CD47 - say, a microbe - the macrophage engulfs and "eats" it.

If a foreign object is too large to eat, it is surrounded by multiple macrophages, which then secrete undesirable chemicals that promote oxidation and inflammation.

Discher's team was able to attach CD47 to plastic nanoparticles, but they wanted something that would be easier to work with. CD47 is a large protein molecule that is difficult to make.

So they also experimented with fragments of CD47, called peptides, which can be made by programming a machine. The researchers identified the smallest protein fragment that would still be recognized by macrophages - what they called a "minimal self" peptide.

"We wanted to strip it down to the bare essence," said Discher, a professor of chemical and biomolecular engineering at Penn.

Then the scientists injected mice with equal amounts of two kinds of particles: those with the peptides attached, and those without. Half an hour later, there were four times as many of the peptide-enhanced particles, indicating that many more of the regular kind had been cleared away.

The researchers also said that when laden with the cancer drug Taxol, the particles with peptides were better at shrinking tumors in mice.

The peptide particles also were better imaging agents. Because the particles lasted longer, the dye attached to them showed up better on a screen.

Another way to delay clearance of particles is to coat them with polymer "brushes," but this approach, already in use, is not very effective, Discher said.

Nanoparticles are a good way to deliver cancer drugs because tumors have immature, leaky blood vessels, so the particles can easily get inside - provided they can evade the immune system. In some current clinical trials, scientists are trying a more targeted approach - particles fitted with designer molecules that home in on the tumor.

One nano-medicine researcher not involved with the Penn study, Andrew Z. Wang of the University of North Carolina, cautioned that the human immune system is more sophisticated than that of mice, so the synthetic "minimal self" passports will not necessarily work as well in people.

Still, the goal is not to have nanoparticles circulate in the body forever. The idea is just to buy more time, said Wang, an assistant professor at UNC's school of medicine.

"The data are very exciting," he said. "Even if it just helps a little bit, it's good."