Dec 17 2010
Nine years ago, scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute detected a subtle shift occurring in the molecular makeup of the most aggressive type of brain tumors, glioblastoma multiforme. With further study, they found that a specific protein called laminin-411 plays a major role in a tumor's ability to build new blood vessels to support its growth and spread. But technology did not exist then to block this protein.
Now, employing nanoparticles as a drug delivery agent, the research team has created a "nanobioconjugate" drug that may be given by intravenous injection and carried in the blood to target the brain tumor. This work, which was led by Julia Ljubimova of the Cedars-Sinai Medical Center in Los Angeles, was published in the Proceedings of the National Academy of Sciences. Dr. Ljubimova is the principal investigator of one of 12 Cancer Nanotechnology Platform Partnerships funded by the National Cancer Institute Alliance for Nanotechnology in Cancer.
The new nanobioconjugate comprises several key components, each with a role in getting a powerful antitumor agent into brain tumors. The nanoparticle that makes up the bulk of this construct is made of a biodegradable polymer known as polymalic acid that is produced by slime molds and that will self-assemble into nanoparticles. The researchers attached to the polymer backbone a variety molecules, each with its own role to play in getting this construct to brain tumors and killing them. One set of molecules enables the resulting nanoparticle to cross the blood-brain barrier, while another helps the nanoparticle enter the cell. A third set of molecules cause tiny compartments inside cells, known as endosomes, to rupture, releasing the nanoparticle into the cell's cytoplasm. Finally, two different antisense oligonucleotides - the actual anticancer agents - block the production of laminin-411. These antisense agents are not toxic to non-malignant cells.
Studies in lab mice show that this system allows large amounts of antitumor drug to accumulate in tumors, significantly slowing the growth of new vessels and the tumors themselves. Tumors in animals treated with the drug were 90 percent smaller than those in a control group. "This nanobioconjugate is different from earlier nanomedicine drugs because it delivers and releases antitumor drugs within tumor cells, not just at the site of a tumor," said Dr. Ljubimova.
"Based on our studies, this nanoconjugate appears to be a safe and efficient delivery platform that also may be appropriate in the treatment of degenerative brain conditions and a wide array of other disorders. It is harmlessly degraded to carbon dioxide and water, nontoxic to normal tissue, and, unlike some drugs, it is non-immunogenic, meaning that it does not stimulate the immune system to the point of causing allergic reactions that can range from mild coughs or rashes to sudden, life-threatening symptoms," Dr. Ljubimova explained. She and her colleagues have formed the company Arrogene to develop this construct for clinical use.
This work, which was funded in part by the National Cancer Institute, is detailed in a paper titled "Inhibition of brain tumor growth by intravenous poly (ß-L-malic acid) nanobioconjugate with pH-dependent drug release." An abstract of this paper is available at the journal's website.