Can nanotech beat cancer?

Cancer will always be with us in some form, but the fear and devastation it causes could be history within a generation. We'll have the tiniest of things to thank for it.

By Eric Smalley, Technology Research News

In 1974, with a newly minted MIT doctorate in chemical engineering, Robert Langer received 20 job offers from oil companies. At the time, developing petroleum and plastic was what chemical engineers did. Langer was looking for something more fulfilling. He turned down all 20 offers and sent out a flurry of applications for positions teaching science education. He got nowhere. "I didn't want to do the first thing; nobody would hire me to do the second," he said.

Next he tried hospitals, but struck out again. Then a coworker mentioned that famed cancer researcher Judah Folkman sometimes hired nontraditional medical researchers. As it turned out, Folkman was looking for someone other than a biologist to devise a way of choking off the blood supply that feeds cancer tumors. Most cancer treatments are far less strategic: they carpet bomb the body with toxins and radiation that destroy any fast-dividing cells, including perfectly health blood and bone marrow cells. Langer's first project for Folkman was developing a way of containing molecules that curtail blood-vessel growth—angiogenesis inhibitors—in microscopic pellets that would slowly release the material into tumors. "I was trying to mimic a cell or organelle that would continuously secrete substances," he said.

Folkman’s gamble paid off. Together Langer and Folkman eventually developed angiogenesis inhibitors that are the precursors to the cancer drug Avastin and dozens of other drugs in clinical trials.

Today Langer is co-director of the MIT-Harvard Center of Cancer Nanotechnology Excellence, which is focused on drug-delivery technologies. It is one of eight centers receiving portions of a $144 million, five-year federal grant to develop new ways to diagnose and treat cancer, in line with the National Cancer Institute's goal of eliminating suffering and death due to cancer by the year 2015. The centers are building the next generation of cancer treatments—smart weapons that home in on cancer cells and cripple or kill them. These smart weapons aren't drugs in the traditional sense. They're nanotechnology: infinitesimal machines capable of slipping through the bloodstream, seeking out specific types of cells and selectively delivering deadly payloads. At about 100 nanometers in diameter—which is 50 times smaller than a red blood cell—they are small enough to pass through a pore in a cell membrane. While the drugs are not expected to eliminate cancer, they could make it a disease as treatable as diabetes or asthma.

Nano package

Several chemotherapy drugs on the market already exploit nanotechnology by packaging anti-cancer compounds in particles that are small enough to slip through cell pores. Not only is the delivery more direct than conventional therapy but the packaging protects the drugs from the watery environment of the body. "I can think of a handful of nanotechnology-ish drugs that are FDA-approved right now," said Omid Farokhzad, a Harvard Medical School researcher and one of Langer's collaborators. These include Doxil, used to treat ovarian cancer, Genexol-PM used against a number of cancers, and Abraxane, used to treat metastatic breast cancer.

That class of drugs also bears the imprint of Langer’s chemical wizardry. In 1994, he and one of his MIT students, Ruxandra Gref, hit on a mix of polymers for a coating that would render the nanoparticles invisible to the immune system. The coating enables the particles to circulate in the bloodstream and reach the cancer cells without being attacked.

But the nanodevices that are working their way toward approval today are much more sophisticated, said Farokhzad. They not only evade the immune system, they also seek out cancer cells and signal when they've found them. Achieving this has been a struggle. The problem is, the more capabilities you give these nanoparticles the harder it is to ensure they are safe and effective.

The better a nanoparticle is at targeting cells, for example, the less stealthy it becomes, and vice versa, Farokhzad explains. If you direct the nanoparticle by attaching the “zipcode” or biological signature of a cancer cell, so to speak, that information also makes the particle more visible to the immune system. Thus, the drug designer has to work on tradeoffs: how much precision to trade for stealth? "That challenge has been the bottleneck... for the entire field."

Two years ago, after some initial success, Langer sent Farokhzad to consult with a scientist at a biotechnology company about the prospects for turning their nanoparticles into drugs that would pass regulatory muster. The company scientist told him there were too many unknowns to make the production process of attaching targeting molecules to a nanoparticle feasible. "We were in a conference room just throwing a lot of ideas on the blackboard... for two or three hours," said Farokhzad. "And then there was a little light bulb that went on."

Stealth mode

Langer and Farokhzad took a cue from evolutionary biology. "A virus looks an awful lot like a nanoparticle," said Farokhzad. Viruses are very efficient at evading the immune system and invading cells. "How do they do that effectively, and how do we mimic that?" he said. "They do it because they evolved."

What evolution draws on is diversity, so Langer and Farokhzad proceeded to catalogue the different types of nanoparticles and their physical and chemical properties. Now they can determine the qualities they need in a nanoparticle– such as size, composition, coating—for a given medical use, then search their library for a match. Instead of trial and error, "we can say a nanoparticle that looks like this—meaning it's got this size and it's got this charge and it's got this many targeting molecules and it's got this many stealth molecules—is one that's going to do the job," Farokhzad says.

Sometime in the not-so-distant future, cutting-edge cancer treatment might go something like this: A physician injects billions of nanoparticles into a cancer patient. As the nanoparticles circulate through the bloodstream their stealth coating cloaks them from the immune system. Once they encounter cancer cells, molecules on the nanoparticles' surfaces fit lock-and-key-fashion with receptor molecules on the surface of the cancer cell. When a nanoparticle opens a cancer cell's molecular lock, the cell pulls the nanoparticle inside through a pore in its membrane. Opening the molecular lock also changes the nanoparticles' fluorescence. After administering the treatment, a doctor could scan the patient for the fluorescent signal indicating that the nanoparticles have found their targets and delivered their payloads.

A nanoparticle bearing a drug or drug cocktail can be designed to deliver its cargo in response to different cues. Delivery could happen when antibody or DNA strands on the particle encounter biological molecules that are specific to the interiors of cancer cells. It could occur when the temperature reaches a certain level. Or it could occur upon encountering the interior of a cancer cell, which is more acidic than the exterior. The timing of release varies as well. Some nanoparticles release the treatment immediately; others slowly dissolve after they’ve entered the cells, releasing the drug over days or weeks.

Farokhzad and Langer have already had some success using the targeting approach. They led a team that developed chemo-carrying nanoparticles coated with aptamers—short strands of RNA or DNA—that home in on proteins in prostate cancer cells. When they tested the nanoparticles on prostate tumors in mice, the tumors were eradicated in five of seven mice and all seven mice survived. In contrast, chemo-carrying nanoparticles without a DNA coating eradicated tumors in only two of seven mice and only four survived. Only one mouse in seven using the chemotherapy drug alone survived. Langer and Farokhzad have started a company, BIND Biosciences, to commercialize their nanoparticle treatment, and they expect to start human trials in 2009.

Flipping switches

Another of Langer's research teams is developing nanoparticles that deliver strands of short interfering RNA, or siRNA, which has shown promise in switching off genes without damaging DNA. (The discovery of this process, called gene silencing, by researchers Andrew Zire and Craig Mello won them the 2006 Nobel Prize for medicine.) In several recent studies, siRNA-carrying nanoparticles have reduced tumor growth in mice.

Daniel Anderson, a senior researcher in Langer's laboratory, has taken it a step further, with a scheme to envelop siRNA in fatty membranes (lipids) that deliver siRNA to cancer cells. "We checked literally thousands of these and found some that work incredibly well," Langer says.

The researchers are testing the siRNA-lipid nanoparticles in monkeys. So far they've been able to turn off genes that play a role in causing cancer, without harming the animals, Langer said. Human liver cancer trials are scheduled for next year.

While Langer and his colleagues are still experimenting in animal models, Jack A. Roth, thoracic surgeon and director of the W. M. Keck Center for Innovative Cancer Therapies at the M. D. Anderson Cancer Center, and his colleagues are already testing an intravenous nanoparticle lung cancer treatment in humans. Their nanoparticles are bubbles of lipids containing DNA to correct a damaged tumor-suppressing gene. These devices, called liposomes, are stable in the bloodstream, ignored by the immune system, and taken up only by tumor cells.

So far, 13 patients with stage IV non-small-cell lung cancer have received the treatment. Biopsies showed that the tumor-suppressing gene was active in the treated patients' tumor cells. Of the eight patients who received multiple treatments, five showed progress and three held stable for three to seven months. The patients, who had all received standard chemotherapy before the trial, survived more than twice the usual seven months for patients receiving a standard second round of chemotherapy. There were no serious side effects. "In the patients we've treated so far it appears very safe," Roth says.

For many types of cancer just about any treatment that works would be revolutionary. The five-year survival rate for lung cancer, for example, is still below 20 percent. Even with the wonders of nanotechnology, Langer admits there isn't going to be a lightning bolt breakthrough like a vaccine for all cancers.

"We're hitting singles; we're not necessarily hitting home runs,” he says. "But it may be you can win the game with a lot of singles."


October 11, 2007

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