January 30, 2006
The AbraxaneŽ Story: A Nanoparticle Platform Delivers Improved Anticancer Activity
By interacting with two biochemical processes common among tumors, nanoparticles made of the human protein albumin, are capable of boosting the amount of anticancer drug available to kill malignant cells. That was the message that Michael Hawkins, M.D., delivered on January 24, 2006, in the latest installment of the National Cancer Institute’s Nanotech Seminar Series.
Hawkins, Chief Medical Officer of American BioScience, Inc., in Santa Monica, CA, presented some of the clinical data for Abraxane®, the first approved drug to use albumin nanoparticles to improve the therapeutic and safety properties of an anticancer agent. On February 7, 2005, the U.S. Food and Drug Administration approved a nanoparticulate formulation of the widely used anticancer drug paclitaxel, for use in patients with metastatic breast cancer who have failed combination therapy. Hawkins also discussed the results of experiments showing how albumin nanoparticles may be able to improve the clinical usefulness of a wide variety of anticancer drugs.
Abraxane, said Hawkins, was formulated to eliminate the safety issues associated with other approved paclitaxel preparations, such as Taxol®, that use various detergents to help the paclitaxel molecule dissolve in water. Solubility in water is essential for administering drugs into the bloodstream. Unfortunately, the detergents used in other paclitaxel formulations can themselves be toxic, requiring that patients receive additional medications to counteract those toxicities. Albumin nanoparticles overcome this solubility issue, taking advantage of the fact that albumin is the body’s natural carrier of molecules that are poorly soluble in water.
Data from clinical trials showed that, indeed, Abraxane was safer than Taxol, as well as more effective, in treating patients with breast cancer who had failed earlier therapies. Hawkins also presented data from subsequent clinical trials demonstrating that Abraxane is also effective at treating non-small cell lung cancer and metastatic melanoma. Based on these data, the company hopes to receive FDA approval to treat these types of cancer, in addition to the approval for breast cancer.
The improved efficacy of Abraxane over Taxol was at first suspected to result simply from the fact that patients could be given larger doses of paclitaxel, thanks to the lack of detergents in the nanoparticulate formulation. But subsequent studies, said Hawkins, found that albumin interacts with two different proteins that actively transport albumin – and the paclitaxel molecules associated with it – into tumors.
The first protein, called gp60, is found on the surface of the endothelial cells that line the interior of blood vessels. This protein binds to albumin, starting a series of biochemical events that results in albumin and the associated paclitaxel, being transported out of the bloodstream, through the endothelial cell and out into the fluid surrounding tumor cells. As a result, paclitaxel is removed from the bloodstream and becomes concentrated in the vicinity of malignant cells. The detergents used in other paclitaxel formulations cannot take advantage of this transport mechanism.
The second protein, called SPARC, is found on the surface of many types of tumor cells, and its presence is associated with a poor prognosis. Hawkins presented data showing that SPARC also binds to albumin. With SPARC, however, the albumin and paclitaxel bound to it remain in the tumor cells. The result is that more paclitaxel ends up in tumor cells thanks to albumin nanoparticles. When Hawkins and his colleagues examined clinical data from 16 patients with head and neck tumors who had been treated with Abraxane, they found that of the 12 patients whose tumors expressed SPARC, 10 responded positively to drug therapy. In contrast, four patients had tumors that did not express SPARC, and only one responded positively. Though this is but a small study, Hawkins said that it suggests that patients with SPARC-positive tumors, that is, those with the worst prognosis, should respond favorably to Abraxane therapy.
Hawkins ended his presentation by discussing his company’s efforts to formulate other water insoluble anticancer drugs into albumin nanoparticles. He also raised the possibility that since gp60 is expressed in lung tissue and in cells lining the intestines, albumin nanoparticles may be useful in creating drug formulations that could be administered by inhalation or orally.
A replay of Hawkins’ presentation is available through the National Institutes of Health webcast archive.