The Power of Small Cures
Thayer researchers help turn nanoparticles and heat into a treatment for cancer.
By Anna Fiorentino
Photographs by John Sherman
When a dog named Carmen was diagnosed with an oral melanoma, there was both bad news and good news. The bad news was that the aggressive tumor could kill her within a few months. The good news was that the black Lab could join a clinical trial of magnetic hyperthermia, a new treatment being developed by the Dartmouth Center of Cancer Nanotechnology Excellence (DCCNE), a collaborative research initiative involving engineers from Thayer School and clinicians from Geisel School of Medicine and Norris Cotton Cancer Center at Dartmouth.
Wedged between her gumline and lip, Carmen’s grape-sized malignancy was the largest that DCCNE researcher Jack Hoopes, a Geisel School of Medicine professor and Thayer adjunct professor, had seen since embarking on trials in thousands of mice and three other dogs. Standing above an anesthetized Carmen in an operating room at Dartmouth-Hitchcock Medical Center (DHMC), Hoopes says, “We’re seeing if magnetic hyperthermia treatment can be adapted to these kinds of larger lesions.”
The first step for Carmen will be surgery to excise as much of the tumor as possible. Then magnetic iron-oxide nanoparticles will be injected into the tumor site to penetrate any remaining cancer cells. The dog will be placed under an alternating magnetic field that will cause the nanoparticles to heat up. The heat will kill the cells that come into contact with the nanoparticles.
“You can allow for a more precise delivery of toxins from the heat to one specific area instead of giving a limited dose of chemotherapy or radiation to a large area of the whole body,” Hoopes says. And unlike chemo, which can stop working or be too toxic to tolerate, magnetic hyperthermia can be repeated as often as needed.
Ideally, magnetic hyperthermia would be a stand-alone therapy, but for now DCCNE researchers are combining it effectively with standard cancer treatments. “We’ve had good success pairing magnetic hyperthermia with chemotherapy, radiation, surgery, or a combination,” Hoopes says, adding that all three dogs treated before Carmen are now cancer-free.
GETTING MAGNETIC HYPERTHERMIA to work in animals is a step toward the DCCNE’s ultimate goal: using magnetic hyperthermia to treat ovarian and breast cancers—including metastases—in humans. Now in the third year of a five-year, $12.8 million grant from the National Cancer Institute, the DCCNE brings together multiple areas of scientific, engineering, and clinical expertise to make that happen.
Materials scientist Ian Baker, who is both director of the DCCNE and Thayer School’s Sherman Fairchild Professor of Engineering, heads up efforts to create new biocompatible iron-oxide nanoparticles that work better than commercially available nanoparticles. His group’s newest nanoparticles are coated with dextran, a kind of glucose. “They heat better than those sold commercially,” says Baker. Producing particles that range in size from 8 to 100 nanometers, his group is characterizing the properties of the particles, including measuring how well they absorb electromagnetic power.
Protein engineers, led by Thayer professors Karl Griswold and Tillman Gerngross, are creating antibodies that couple with the iron-oxide nanoparticles and carry them to cancer cells. The group’s in-vitro studies have shown promise. “Depending on the types of nanoparticles and cancer cells we are examining, we can get, in some cases, two orders of magnitude better targeting having an antibody on the nanoparticle versus not having an antibody on it,” says Griswold. In the group’s early studies of ovarian cancers in mice, the antibodies are able to deliver nanoparticles to some but not all tumors. In studies of breast cancers in mice, only small nanoparticles arrive at the tumor. The group will continue to tailor the coupling of antibodies and nanoparticles until they can target cancers from different patient populations and better understand the biological complexities of tumor targeting. “Our current results highlight the need to carefully match particle design with the intended clinical application,” says Griswold.
Another team of researchers, led by Geisel radiology professor and Thayer adjunct professor John Weaver, is developing sensing methods to provide the hyperthermia systems the information they need to be effective. “The first piece of information required is where the nanoparticles are within the tissue. We have developed methods of measuring the nanoparticles’ relaxation time, which characterizes their ability to rotate freely. It provides information about which microscopic compartment the nanoparticles are in—vascular, extracellular, intracellular—and how tightly the nanoparticles are bound to the surrounding structures,” says Weaver. “The second piece of information required is how many nanoparticles are present. We have tools that correct for relaxation effects so the number of nanoparticles in a given volume can be measured. The third, and possibly most important, piece of information is how hot the tissue is during the treatment. Blood flow is very efficient at pumping heat out of tissue, so it is very difficult to predict what temperature is being achieved with a given power. We have tools that are able to measure the temperature during the hyperthermia application so you know exactly how hot the tissue is and can adjust the treatment to achieve therapeutic temperatures.”
One of the DCCNE’s several Geisel colleagues, Steven Fiering, a professor of microbiology, immunology, and genetics, has demonstrated that nanoparticles carry the body’s own pathogen-fighting phagocytic cells into tumors with them. Fiering’s group has also shown that when mice with melanomas are treated with magnetic hyperthermia, their immune systems are able to slow or block recurring tumors.
Dartmouth isn’t the only National Cancer Institute-funded Center of Cancer Nanotechnology Excellence. There are eight others, including Stanford, Johns Hopkins, and MIT. “Other centers are researching nanotechnology, and two or three are working together,” says Baker, “but we’re the only center with multiple projects focused on a single topic: magnetic hyperthermia.”
IN THE OPERATING ROOM, Hoopes watches as Dr. Eunice Chen, a DHMC surgeon, excises as much of Carmen’s tumor as she can with a cauterizing scalpel. Hoopes hands Chen a syringe filled with a black fluid containing about 80 milligrams of nanoparticles. “Inject the nanoparticles into the tumor bed. Get as many as you can in,” he says.
Chen rotates Carmen’s head so the nanoparticle-laced fluid won’t trickle out of her mouth. In the future, the team will likely use a new slow-release gel that will prevent leakage. Ben Cunkelman Th’13 ’14 and Robert Collier ’13 Th’13 invented the gel, made of a starch polymer, in a course Hoopes teaches at Thayer, ENGS 56: “Introduction to Biomedical Engineering.” The students applied for a patent for the gel in February—one of nine patents associated with the DCCNE so far. “The idea is to apply the gel onto a tumor margin after surgery and after a certain amount of time the gel will degrade, leaving the nanoparticles on the margin,” Cunkelman explains.
But for now, Chen injects the nanoparticles into the tumor site and lets them settle for a half hour or so. Then Carmen’s bed is rolled across the hall into Hoopes’ laboratory. Hoopes positions Carmen’s head over a grid of red dots that looks more like a child’s game than an alternating magnetic field. He and Thayer Ph.D. Innovation Program student Alicia Petryk ’06 Th’07 ’08 ’13 attach four probes to Carmen’s smooth, black coat and inside her mouth, connecting her to a thermal camera that will monitor her temperature. The magnetic field is applied to the nanoparticles, raising their temperature a tenth of a degree every 10 seconds. “Inappropriate use of the magnetic field could result in dangerous toxicity from overheating of the patient’s outer-circumferential body tissues if the electromagnetic frequency and field strength is too high or incorrectly matched, so we’re being conservative,” says Hoopes.
Demonstrating that magnetic hyperthermia can be done safely and effectively will be one of the many hurdles involved in securing FDA approval to treat humans. “We think the magnetic iron-oxide nanoparticles will be very safe at the doses we are using,” says Hoopes. “Similar nanoparticles have been used to treat anemia and as an MRI contrast agent in the past, and neither have shown any toxicities.”
Hoopes keeps monitoring the probes and adjusting Carmen’s head to regulate the direct heat she receives. After 45 minutes, Hoopes powers down and Petryk disconnects the probes. Carmen begins to wake from the anesthesia.
At last Carmen is released to her owner, who tells Hoopes, “It’s been a real honor to be part of this.” Hoopes reassures him that the dog should have a new lease on life.
“But if we have to,” Hoopes adds, “we can always treat her again.”
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