A new treatment strategy using targeted nanoparticles to block metastasis with anti-cancer drugs leads to good results using significantly lower doses of toxic chemotherapy, with less collateral damage to surrounding tissue, according to a collaborative team of researchers at the Center of Nanotechnology for Treatment, Understanding, and Monitoring of Cancer at the University of California, San Diego. In designing this system, the investigators, led by David Cheresh, Ph.D., have identified what may become a generic method for using nanotechnology to target metastasis.
In a study to be published online in advance of print publication in the Proceedings of the National Academy of Sciences, the investigators report that the lipid-based nanoparticle carrying a payload of doxorubicin, a widely used chemotherapy agent, homes in on a protein marker called integrin áíâ3, which is found on the surface of certain tumor blood vessels. This integrin, which binds strongly to a targeting molecule known as RGD, is associated with development of new blood vessels necessary for tumor growth and metastasis.
The team found that the RGD-targeted nanoparticle-doxorubicin combination didn't have much impact on primary tumors. Surprisingly, however, this formulation did stop pancreatic and kidney cancers from metastasizing throughout the bodies of mice. The researchers showed that a greatly reduced dose of chemotherapy can achieve the desired effect because the drug selectively targets the specific blood vessels that feed the cancerous lesion and kills the lesion without destroying surrounding tissue.
"We were able to establish the desired anti-cancer effect while delivering the drug at levels 15 times below what is needed when the drug is used systemically," said Cheresh. "Even more interesting is that the metastatic lesions were more sensitive to this therapy than the primary tumor.
"Doxorubicin is known to be an effective anti-cancer drug, but has been difficult to give patients an adequate dose without negative side effects," Cheresh said. "This new strategy represents the first time we've seen such an impact on metastatic growth, and it was accomplished without the collateral damage of weight loss or other outward signs of toxicity in the patient."
Cancer metastasis is traditionally much more difficult to treat than the primary tumor, and is what usually leads to the patient's death. Because metastasis is more reliant on new blood vessel growth, or angiogenesis, than established tumors are, Cheresh theorized that targeting the anti-cancer drug to the sites of new blood vessel growth has a preferential effect on metastatic lesions.
"Traditional cancer therapies are often limited, or non-effective over time because the toxic side effects limit the dose we can safely deliver to the patient," said Cheresh. "This new drug delivery system offers an important advance in treating metastatic disease."
In a second paper, researchers at Harvard Medical School report on their development of the first oral, broad-spectrum angiogenesis inhibitor. This inhibitor, specially formulated using nanoparticles to improve the body's handling of the active ingredient, has yielded promising results in blocking metastasis and killing tumors in animal models of human cancer. The data from initial studies using this drug formulation, which the investigators have named Lodamin, appear in the journal Nature Biotechnology.
In addition to Lodamin's activity as an antiangiogenesis agent, this nanoparticulate drug formulation appears to be nontoxic-a characteristic that, combined with the drug's ability to be taken orally, suggests that it may be useful as a preventive therapy for patients at high risk for cancer or as chronic maintenance therapy for a variety of cancers. Maintenance therapy with this drug may prevent tumors from forming or recurring by blocking the growth of blood vessels to feed them. Lodamin may also be useful in other diseases, such as age-related macular degeneration and arthritis, that involve aberrant blood vessel growth.
Developed by Ofra Benny, Ph.D., of Harvard Medical School and Children's Hospital in Boston, in collaboration with the late Judah Folkman, M.D., Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, M.D., Ph.D., then a fellow in Folkman's lab and now a faculty member at Harvard Medical School. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions. Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.