A team of researchers has developed a molecular-sized atomic generator that slips into cancer cells like a tiny Trojan horse and produces extremely small but potent radioactive particles that destroy those cells without apparent toxic side effects, according to a report in the 16 November issue of the journal, Science.
David A. Scheinberg of the Memorial Sloan-Kettering Cancer Center and colleagues used the nanogenerators to kill a variety of human cancer cell types in the lab, and to treat solid prostate and widely disseminated lymphoma tumors in mice, significantly prolonging their survival.
The research team hopes to file an application with the U.S. Food and Drug Administration (FDA) to begin human trials of the nanogenerator by next year, says Scheinberg.
The generator consists of a radioactive atom of actinium chemically harnessed to an antibody that zeros in on and penetrates only specific cancer cells. Inside the cell, the actinium decays by giving off alpha particles--very small, high-energy particles that rip through the cell and destroy it. Actinium's decay produces a series of three "daughter" atoms, each of which emits its own alpha particle as well.
"These are extraordinarily potent drugs. One atom will kill a cell," says Scheinberg.
At the same time, the internalization of the generators also helps to contain actinium's toxic decay daughters within the cell, making them less likely to escape to other sites in the body like the kidneys or intestines.
By attaching the generators to a variety of different antibodies, the Science study authors were able to kill human leukemia, lymphoma, breast, prostate, and ovarian cancer cells with very small doses of the generators--one trillionth of the standard unit of radioactive decay. A single, nontoxic, larger dose injected into mice with prostate and lymphoma tumors caused tumors to shrink and prolonged the mice's survival by several months in some cases.
Although it's too early to know what doses might be optimal in treating human cancers, "the doses will probably be so small that the injections could be done in a doctor's office or outpatient hospital clinic," says Scheinberg.
In previous research, Scheinberg and colleagues had targeted alpha particles to cancer cells using bismuth atoms generated outside of cancer patients. Radioactive bismuth has a relatively short half-life (the time it takes for half of a radioactive sample to decay) of 46 minutes. This short window of potency for atoms generated outside the patient meant that the bismuth therapy was limited in its delivery to only the most accessible cancer cells, and could only penetrate small tumors.
So the scientists searched for a better alternative--a radioactive atom with a more appropriate half-life and lots of alpha-emitting daughters. Once actinium--with a half-life of ten days--became the candidate, the researchers then had to figure out a way to attach it in a stable fashion to an antibody. Solving these two problems took eight years, says Scheinberg.
Actinium's longer half-life means that the current nanogenerators could be manufactured at a central pharmacy and shipped throughout the world, making drug preparation potentially more efficient and less expensive, say the Science authors. The longer half-life also suggests that the actinium generators could be used to penetrate larger tumors.
By bringing the nanogenerator's firepower directly inside the cancer cells, the researchers were able to realize other benefits as well. The trail blazed by an alpha particle is two to three cell diameters wide, so any hit from inside or outside the cancer cell will kill it. The likelihood of a direct hit improves, however, once the nanogenerator is inside the cell.
"The odds of an alpha particle hitting a cell are 100 percent if the particle generator is inside the cell, but only 30 percent if the nanogenerator binds to the cell's outer surface," says Scheinberg.
Some of the nanogenerators may work on multiple types of cancers, but it's more likely that a variety of different antibodies--or other "vehicles" such as small molecules or protein peptides--will be used to specifically target different cancers, say the researchers.
The other members of the research team include Michael R. McDevitt, Dangshe Ma, Lawrence T. Lai, Paul Borchardt, Karen Wu, Virginia Pellegrini, Michael J. Curcio, and Matthias Miederer at Memorial Sloan-Kettering Cancer Center, New York, NY; Jim Simon and Keith Frank at Dow Chemical Company, Freeport, TX; and Neil H. Bander at New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, NY. This research was supported in part by the National Institutes of Health, the CaPCure Foundation, the Lymphoma Foundation, the Cure for Lymphoma Foundation, the Gabrielle Rich Foundation, the Doris Duke Charitable Foundation, and the Pepsico Foundation.
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Science