Making a little progress: nanotechnology takes on cancer.

In September 2004, the National Cancer Institute announced an initiative to bring new blood to an old and desperate fight. Called the NCI Alliance for Nanotechnology in Cancer, the initiative will wager $144.3 million over the next 5 years that nanotechnology will open entirely new and effective strategies for diagnosing and treating cancer. It's a well-funded sign that expectations for nanotech solutions to cancer extend to the highest governmental levels, and it comes at a time when the battle against the disease seems to be at a standstill. Unlike death rates for heart disease and stroke, which have declined drastically, cancer mortality hasn't changed since the 1950s.

"We are looking at new technologies to help change that situation,' says Piotr Grodzinski, director of the cancer-nanotechnology program at NCI.

Nanotechnology, broadly defined as the engineering of devices on the scale of tens to a couple-hundred nanometers (nm), holds promise for cancer detection and therapy for two main reasons: size and function. Nanoscale devices, often referred to as nanoparticles, are small enough to travel through the bloodstream and gain access to tumors. The devices can be designed to specifically target and enter tumor cells. Once inside, they can deliver any number of payloads, from agents that improve cancer detection to treatments such as drugs or genes.

"If you want to pack multiple functions into something that can travel in the bloodstream, you have to have nanoparticles," says Mauro Ferrari, a cancer nanotechnologist at Ohio State University in Columbus and an adviser to NCI. "Everything that will impact cancer in the future, in my mind, will have nanocomponents."

GETTING A GOOD LOOK A maxim of cancer medicine is that the earlier you can detect and diagnose the disease, the better the chances of a favorable, lasting outcome. One of the researchers applying nanotech principles to this idea is Jinwoo Cheon, a chemist at Yonsei University in Seoul, South Korea. He's been developing nanoparticles out of iron oxide with the goal of making magnetic resonance imaging (MRI) capable of picking out smaller tumors than it currently can.

In MRI, a magnet alters the spin of hydrogen protons, which then emit radio signals as they revert to their original spins. The protons in different tissues of the body revert at different rates, and a computer can assemble those differences into images of organs. Nanoparticles with magnetic properties, such as iron oxide nanocrystals, usher the protons to their original spins much faster than unmagnetic particles do. This quick return has the effect of adding contrast to the image, says Cheon.

He and his group wanted to target the particles to cancer cells, so that small tumors could be distinguished within organs in an MRI image. The researchers report in the Sept. 7 Journal of the American Chemical Society that they made 9-nm crystals of iron oxide and then tacked on an antibody that binds specifically to breast cancer cells. The iron oxide-antibody complexes were 28 nm in diameter. The researchers tested these targeted contrast agents by injecting them into the tail veins of mice that had human breast cancer cells implanted in their thighs. Unlike the MRI images of mice that received untargeted nanoparticles, the images of animals getting targeted nanoparticles revealed the cancer.

Quantum dots are another type of nanoparticle poised to provide vivid pictures of cancer. These nanoscale semiconductor particles have such a tiny volume that they're governed by quantum mechanical effects. The energies of the dots' electrons become "quantized" explains Shuming Nie, a biomedical engineer and a chemist at Emory University and the Georgia Institute of Technology, both in Atlanta. The electrons change energy levels in discrete steps, rather than sliding between levels.

Adjusting the particles' sizes creates probes that, when stimulated by light, emit distinct amounts of energy, or different colors of light. With quantum dots, "we can... excite as many as 10 colors simultaneously,' says Nie.

Targeting the different-size quantum dots to various types of cancer cells raises the possibility of "detecting multiple tumor cells by using multiple colors labeled with different [cancer-seeking] antibodies," he adds. The probes are bright enough to shine through the skin.

In the August 2004 Nature Biotechnology, Nie and his team reported on their quantum dot-probes made of cadmium selenide decorated with antibodies that bind to prostate cancer cells. The probes revealed the cancer in mice as red blobs. Cadmium is a poisonous metal, however, so until long-term toxicity studies of the nanoparticles are conducted, use of quantum-dot probes will be limited to animals and tissue samples.

BATTLE PLANS While researchers are pursuing a number of nanotechnology treatments, they're all variations on a theme: targeted cancer killing. "If you can kill cancer cells without affecting normal cells," says Hongjie Dai, a chemist at Stanford University, "that is the Holy Grail," Among the cast of nanoparticle characters in this work are dendrimers, carbon nanotubes, and liposomes.

James R. Baker Jr., a physician and biomedical engineer at the University of Michigan in Ann Arbor, works with dendrimers, spherical polymer particles less than 5 nm in diameter. They have many chemically active branches emanating from their cores-structures that are perfect for holding drugs and other molecules. To target dendrimers to cancer cells, Baker's group attached the vitamin folic acid to the particles. Cancer cells need a large supply of the vitamin to maintain their rapid growth, explains Baker, so they have many folic acid receptors on their membranes. Breast, kidney, lung, and several other types of cancer cells are particularly rich in these receptors.

Baker's team also added the chemotherapy drug methotrexate to the folio acid-loaded dendrimers. The researchers then injected the targeted drug-dendrimer complexes intravenously into mice riddled with human epithelial-cell cancer. As reported in the June 15 Cancer Research, the scientists found that the complexes, which are less than 20 nm in diameter, homed in on the cancer cells. This improved the drug's efficacy: The tumors in the mice receiving the targeted therapy grew much more slowly than did those in mice given only methotrexate or an untargeted drug-dendrimer combo. The homing effect also appeared to reduce the drug's side effects, such as appetite loss. Baker says that his group is hoping to begin trials of the complexes in people during the spring of 2006.

Carbon nanotubes, which are indeed tiny tubes of carbon, follow a different therapeutic path. They burn their way through cancer. The 150-nm-long, 2-nm-diameter tubes strongly absorb near-infrared light and quickly turn the energy into heat, explains Dai. Focusing a near-infrared laser on a solution containing nanotubes brought the water to a boil in 4 minutes, he reports.

Because flesh is transparent to light in this wavelength range, targeting nanotubes to cancer cells and then hitting them with a near-infrared laser could turn the tubes into weapons that kill the cells with heat. The same laser light would pass through the normal tissue without harm. "It's a new type of radiation therapy,' says Dai.

Dai's group also turned to folic acid molecules for their cancer-seeking talents. The team fastened the molecules to carbon nanotubes and then tested the targeted tubes' lethality on a cancer cell line and a normal cell line. The cancer cells took up folic acid-bearing nanotubes, but the normal cells didn't. A subsequent 2 minutes of radiation with a near-infrared laser killed only the cancer cells, the researchers report in the Aug. 16 Proceedings of the National Academy of Sciences.

Dai's group plans to design nanotubes with a different targeting molecule--an antibody that seeks out breast cancer cells--to test the treatment in mice bearing human breast tumors.

Liposomes, tiny lipid sacs, can also be designed to target cancer cells. For the past 9 years, Esther Chang and Kathleen Pirollo, molecular oncologists at Georgetown University Medical Center in Washington D.C., and their colleagues have been developing a tumor-specific liposomal-delivery system, and the team is about to begin testing it in cancer patients.

The researchers use liposomes to deliver a gene called p53 to tumor cells. Normally, if a healthy cell acquires too many mutations to develop properly, the p53 gene will initiate cellular suicide. If this gene stops working, however, the cell keeps growing and can become malignant. The absence of a functioning gene can also make tumor cells resistant to radiation and chemotherapy.

Adding functioning p53 to cancer cells can resensitize tumors to these cancer treatments, says Chang. "If you can make the conventional therapies more effective, you may be able to reduce the amount of radiation or chemo you give to a patient," she says. That's a longstanding goal for oncologists because the treatments' side effects can be severe.

Chang, Pirollo, and their coworkers attached to liposomes an antibody fragment that's similar to transferrin, a molecule that normally carries iron into cells. Tumor cells need a great deal of iron to fuel their rapid growth, so many types of cancer cells carry abundant receptors for transferrin, says Pirollo. Since the receptors usher iron into the cells, the action carries the liposomes' load of working p53 inside.

In mouse studies over almost a decade, a combination therapy of such p53 delivery and radiation treatment eliminated prostate tumors and head-and-neck tumors. "The mice died of old age, cancer-free," says Pirollo. She and Chang recently received Food and Drug Administration approval to do preliminary tests of the liposomes in patients with advanced solid tumors.

Other potential contents for nanoscale liposomes include a combination of chemotherapy agents and drugs that starve tumors by halting blood vessel growth, or angiogenesis, within them. Often, when used at the same time, these two classes of drugs work at cross-purposes, says Ram Sasisekharan, a biological engineer at the Massachusetts Institute of Technology. "Once you shut down the blood vessels, how [does chemotherapy] access the tumors?" he asks.

Sasisekharan's answer was to create a two-part liposome that's 80-200 nm in diameter. An inner polymer nanoparticle, linked to a chemotherapy drug, is encapsulated in a liposome, and the space between is filled with an anti-angiogenesis drug. The liposome first releases its anti-angiogenesis payload into the tumor's vascular system, shutting it down. This traps the inner core at the site of the tumor, where it releases its cancer-killing cargo. As the researchers report in the July 28 Nature, this timed-delivery strategy kept 80 percent of mice with melanoma or lung cancer alive for longer than 60 days. In contrast, mice given simultaneous, conventional doses of the two drugs died after 35 days. The researchers are now doing extensive toxicity studies of the liposomes, with the goal of testing their experimental treatment in cancer patients within a few years.

SAFE AND SOUND? Despite progress, cancer nanotechnology still has many issues to address. For one thing, researchers say, there's a need for standardized techniques that can produce nanoparticle-based complexes that are uniform in size and structure. Only then could researchers be confident that data from various studies of a particular nanodevice are comparable.

Nanoparticles also pose a tricky regulatory scenario, says Ferrari. They could be considered drugs, biological agents, or medical devices, which complicates the approval process. NCI is working with FDA to figure out how nanotech diagnostics and treatments for cancer should be approved, says Grodzinski. Furthermore, NCI has set up a Nanotechnology Characterization Laboratory to develop reproducible testing protocols.

If cancer nanotechnology does live up to its promise, the greatest impact the field may have is in how society views cancer. "What we'd like to do is turn cancer into a [controllable] disease like diabetes," says Baker.

Adds Ferrari, "I really think we have the ability to turn any cancer into something that we can live with for a long time without a significant loss to quality of life. Turning cancer into a chronic, manageable disease is a realistic expectation in the next decade."