A decade ago in Chelmsford, Mass., a military technology development company known as Triton Systems invented a new method for battlefield repairs of body armor and other composite materials. The method uses a resin imbued with nanoparticles designed to heat up when exposed to a magnetic field.
Triton scientists wondered: Could such particles also be used to heat and destroy cancer cells?
The question led to a spinoff company, Triton BioSystems, formed in January 2002, and a collaboration with Sally DeNardo and other scientists in the Radiodiagnosis and Therapy Program at UC Davis Cancer Center. DeNardo, a professor of internal medicine and radiology, is among the world's top experts in radioimmunotherapy, in which radiation is delivered directly to cancer cells.
For the last four years, she has explored the potential of Triton's Targeted Nano-Therapeutics (TNT) system in her laboratory at UC Davis Medical Center, using a mouse model of human breast cancer. "This technique allows us to use what we already know about attaching radioactive molecules directly to cancer cells," DeNardo said. "But this avoids the marrow suppression that can result from using high therapeutic levels of radioactivity."
In the UC Davis experiments, DeNardo creates bioprobes by equipping magnetized, iron-oxide nanospheres with radiolabeled monoclonal antibodies that she has previously studied in breast cancer patients. The antibodies are engineered to lock onto specific targets on the surface of breast cancer cells. Trillions of the bioprobes are then infused into the bloodstreams of laboratory mice that bear human breast cancer cells. Once the probes have searched out and locked onto the malignant cells, an alternating magnetic field is applied to the tumor region, forcing the magnetic nanospheres to change polarity thousands of times per second, instantaneously generating heat within the probes.
In two papers published last fall, DeNardo and her collaborators — including her husband, professor emeritus Gerald DeNardo, also a luminary in the field of radioimmunotherapy — showed that the trademarked TNT system effectively locks onto human breast cancer cells grafted onto lab mice. The group also showed that the treatment system can generate enough heat to shrink the tumors without harming the mice.
DeNardo and her colleagues have now completed a larger animal trial that confirms these results. The new study, due to be published later this year, also shows that researchers can measure bioprobe concentration by imaging the tumors and can use the information to accurately predict how much of a tumor will be destroyed. This will be critical for calculating the right dose of bioprobes to give a patient.
Pioneer in radioimmunotherapy
Sally DeNardo was the subject of a lengthy profile in the International Journal of Oncology earlier this year. The profile cites her "unique leadership" and "seminal studies" in the field of radioimmunotherapy, noting that she was the first investigator to use monoclonal antibodies in the delivery of radioimmunotherapy when she generated monoclonal antibodies against mouse melanoma in 1979.
In 1985, she successfully treated patients with non- Hodgkin's B-cell lymphoma and chronic lymphocytic leukemia using radiolabeled monoclonal antibodies, showing for the first time that radioimmunotherapy could be effective in these malignancies.
In 1990, she described the treatment of the first patients with breast cancer using radioimmunotherapy with a biologically active antibody and provided the first evidence of a vascular target strategy for enhancing tumor uptake of a drug.
DeNardo is on the editorial boards of five international journals, has published more than 300 scientific articles, chapters and reviews and has been recognized by multiple awards, including the Benedict Cassen Prize from the Society of Nuclear Medicine in 2000, in which she and Gerald DeNardo were acclaimed for their groundbreaking work in the radioimmunotherapy of lymphoma.
Samuel Straface, president and chief executive officer of Triton BioSystems, said the company approached the DeNardos because of their experience in radioimmunotherapy and their track record in conducting the research that sets the stage for U.S. Food and Drug Administration approval of new drugs. UC Davis' reputation for multidisciplinary collaborations was also a draw.
"We were looking for a partner who had prior experience in delivering molecular payloads to cancer cells," Straface said. "Biological targeting is what the DeNardos are famous for."
According to Straface, the iron-oxide bioprobes used in the TNT system should be eliminated through the body's normal iron metabolism, passing harmlessly from the body after a couple of weeks.
Because the bioprobes are inactive when infused into the body, he believes the approach will prove safer than chemotherapy or radioimmunotherapies that rely on the delivery of radioisotopes or chemotoxins via antibodies.
Clinical trials in human patients will be needed to settle these and other questions. The careful groundwork laid by DeNardo and her colleagues sets that stage.