For decades, the war on cancer has been waged with the medical equivalent of buckshot: Toxic drugs are injected into patients and then scatter, with only a small fraction landing on the intended target. Tumors may shrink, but patients often suffer horribly.
Now, inside laboratories in Massachusetts and around the world, scientists are developing cancer weapons that are made tiny enough to pierce cancerous cells and smart enough to spare healthy ones.
The devices, often made of common materials like plastic or rust, hold the promise of delivering payloads of powerful medication directly to tumors. Other diminutive devices would act like glowing beacons, quickly indicating when cancer has spread or returned.
The federal government is investing nearly $145 million in the quest, with $20 million of that devoted to research at the Massachusetts Institute of Technology and Harvard University. And the pace of discovery is accelerating: Already, one cancer-detection method developed at Massachusetts General Hospital is awaiting approval by federal regulators.
Still, the research must solve a host of medical and engineering riddles demanding the expertise of cancer doctors, as well as chemists, electrical engineers, and computer scientists.
"We're dreaming about how cancer [treatment] can be changed," said Dr. Sangeeta Bhatia, a physician and engineer at MIT. "But it has to be borne out in patients - that's the ultimate challenge."
This is a field in which size matters. The smaller, the better. Just how small? Think of a tennis ball. Now, think of something tens of millions of times smaller. That is the size of some of the tumor-detecting and drug-delivering vehicles being developed.
The devices are known as nanoparticles, and at their smallest, they are single crystals of a material. A favorite choice among scientists is iron oxide, better known as rust. Even if hundreds of the particles are suspended in liquid in a test tube, they are barely visible.
But their potential is huge.
Doctors have long been frustrated by their inability to know before they operate whether cancer has colonized surrounding lymph nodes. If cancer has traveled from a man's prostate to the adjacent tissue, for example, a doctor might very well opt for radiation rather than surgery.
"The goal of the surgery is cure," said Dr. Mukesh Harisinghani, a Massachusetts General Hospital radiologist. "But if I expose the patient to the [risk] of the surgery and he still has disease present elsewhere, I'm not curing him."
So the Mass. General scientists enlisted iron oxide nanoparticles to go hunting for cancer-riddled lymph nodes.
The nanoparticles are pumped into patients. If there's no cancer present, the slivers of iron are absorbed into the lymph nodes, which appear black on an MRI scan, signaling health. By contrast, if cancer has colonized the lymph nodes, the MRI will turn white, because malignant cells can't consume the iron nanoparticles.
The approach has been successfully tested in patients with prostate, breast, colon, and testicular cancer, and its wider use is awaiting approval by the US Food and Drug Administration.
"The availability of new imaging technology utilizing nanoparticles is very promising in allowing physicians" to more accurately determine the extent of a malignancy and offer patients the best treatment options, said Dr. William Kyu Oh, a prostate cancer specialist at Dana-Farber Cancer Institute.
In Bhatia's lab at MIT's David H. Koch Institute for Integrative Cancer Research, they are working on iron oxide nanoparticles that would be even more clever. The researchers want their particles to deliver medication as well as detect cancer. Like microscopic balloons, the particles could have the drug embedded inside, or glued onto the exterior.
But how do the thousands of nanoparticles get to their intended address, the tumor? It's a lot like making sure a letter gets to the right address. You have to know the ZIP code.
Bhatia and other researchers are coming up with a catalog of specific "addresses" for tumors by analyzing telltale molecular changes that occur in the network of blood vessels feeding cancer cells. The codes, once cracked, can then be chemically attached to the iron oxide nanoparticles to assure proper delivery.
But coming up with the right address solves only one problem. Scientists must also make sure the medication doesn't fall off before reaching the tumor, and the nanoparticles must sneak past the liver, the organ trained to filter out foreign invaders.
Another MIT scientist, Michael Cima, is working on a different detection approach that takes iron oxide and places it inside a Lilliputian piece of plastic shaped like a hockey puck. Currently being studied in mice, it would be implanted at the same time a tissue biopsy is performed, and left behind.
"Some of these devices are going to be small enough that you don't care if the plastic dissolves [or stays in your body]," Cima said. "Which would you rather have? Cancer, or a little piece of plastic left in you?"
The chunk of plastic has holes on its surface big enough to allow a cancer-related protein to enter and be detected, but small enough to prevent the iron oxide from escaping. It's important for the iron oxide nanoparticle to remain inside because it carries the lure that attracts the cancer protein.
The plastic would remain in place so that MRI tests could be performed periodically to see if a benign growth has turned malignant or whether a tumor has spread. Cima's lab is developing an even more sophisticated technique to allow the device to be monitored with a wearable detector that doctors could use to quickly identify cancer's spread.
He is also doing preliminary work on implantable devices that would deliver medication directly to tumors. Building such sophisticated, small machinery requires microengineering akin to what is used to make iPods. Much like the slim music machines, the implantable cancer detectors and drug-delivery devices must withstand the body's equivalent of being stepped on or dropped.
"A lot of research went into the iPod to make it mechanically sound so that you can drop it, and it still works," Cima said. "We tried to use the same kind of approach with the design of medical devices."
Formidable obstacles exist before nanoparticles can be used widely in the detection and treatment of cancer. For one, researchers must prove that the materials they're using won't harm patients. Certain agents, such as plastics and iron oxide, are already widely used for other purposes in patients, but there's far less experience with those materials at such a tiny scale, fueling fears that the material's properties may change.
Additionally, adding a drug or a molecular address label to the particles triggers the need for more safety reviews.
Researchers must also guarantee that any new treatments meaningfully improve on options that already exist. And just like any screening method, doctors will need to ensure that they do not operate or give patients drugs when simply monitoring a troubling growth would suffice.
"If you recognize it immediately, it doesn't mean you need to treat it immediately," said Piotr Grodzinski, director of the National Cancer Institute's Alliance for Nanotechnology in Cancer. "It means you have an opportunity to be aware of it and monitor it."
Dr. Robert Cima, brother of MIT's Michael Cima, witnesses the potential for nanodevices every day at the Mayo Clinic in Minnesota, where he is a gastrointestinal surgeon.
When he removes a tumor from a patient's colon, he cuts a wide swath around the growth to make sure he doesn't leave any cancer behind. But if he knew before operating that the areas around the tumor were cancer-free, the scope of surgery could be reduced and hospital stays and complications would decrease.
"There have been a lot of times when I call Mike and I tell him, 'I'm in the trenches, and you're in the ivory tower. I'm doing this work, and I know I can do it better if I had better solutions,' " Cima said.
"I look for him to give me better solutions."
Stephen Smith can be reached at firstname.lastname@example.org.