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Anti-Cancer Nanoparticles: Scientists Design Gene-Tipped Tumor Regressor "Smartbombs"

group of researchers from The Scripps Research Institute has demonstrated what, in principle, could be a new way of treating cancer and several other diseases where angiogenesis occurs. Angiogenesis, the formation and differentiation of new blood vessels, is a crucial process in cancer, and, when blocked, improves a patient's prognosis.

In cancer-related angiogenesis, tumors develop their own blood supplies by causing cells that line blood vessels to proliferate, forming new vessels and bringing more blood to the tumor. The increased oxygen and nutrients the tumors receive allows them to grow and enable certain "metastatic" cells to leave the tumor, enter the bloodstream, migrate to other tissues of the body, and establish more tumors.

In an article appearing in the journal Science, The Scripps Research Institute investigators combined a gene that shuts off angiogenesis with a 50- to 100-nanometer-sized particle that selectively targets the cells that form new blood vessels in cancer tumors. This approach combines gene delivery with specific vascular targeting thereby effectively disrupting the blood supply of tumors without influencing the normal blood vessels or any other tissue.

CUTTING OFF A TUMOR'S SUPPLY ROUTES

This anti-cancer nanoparticle can be likened to a smart bomb that delivers its multiple warhead genetic payload into endothelial cells that proliferate during angiogenesis -- which is the medical equivalent of cutting off a tumor's supply routes. Once angiogenesis is stopped, the tumor cells starve, and the tumor is ultimately destroyed.

Anti-angiogenics have been known and studied for many years, but this anti-cancer nanoparticle is a new type of anti-angiogenic. Unlike other, "systemic" angiogenesis blockers, which become diffused throughout the blood steam upon injection, the nanoparticle-targeting vehicle directs itself to areas of the body where the tumors exist and where local vascular cells are expanding to form new blood vessels. The nanoparticle homes in on these cells and drops off multiple copies of a gene that effectively blocks angiogenesis and kills tumors.

"We saw strong regression of large tumors in every system we looked at," says The Scripps Research Institute Professor David Cheresh, Ph.D., of the Department of Immunology, who led the study.

In the current paper, the investigators first report how they successfully delivered nanoparticles with "reporter" genes -- such as those encoding for luciferase or green fluorescent protein, proteins that glow like the tail of a firefly. These reporter genes allowed dramatic demonstrations of the specific targeting of the nanoparticles to tumors. The tumors glowed green under a microscope.

TOWARDS THERAPIES

Cheresh and his colleagues then combined the nanoparticle with the mutant Raf gene and tested whether they could regress tumors in vivo, and they found the technique worked. Wherever there were metastatic lesions in the lung or liver, the Raf gene eliminated them.

The next step, says Cheresh, is to develop the technique in a more refined way as a general approach towards cancer therapy. The method might prove efficacious alongside some existing chemotherapy, for instance, to reduce the toxicity of existing anti-cancer drugs.

And, he adds, these nanoparticles may be useful in several other diseases where angiogenesis plays a major role -- like heart disease, stroke, rheumatoid arthritis, and certain types of blindness in elderly patients and in patients with diabetes.

In the case of cancer, arthritis, and blinding eye disease this approach will be used as described to destroy newly sprouting vessels. However, following stroke and heart attack, new blood vessel growth is desirable. Therefore, this approach can be used to target pro-angiogenic genes to these sites and in so doing promote the rapid regrowth of blood vessels.

The research article "Tumor Regression by Targeted Gene Delivery to the Neovasculature" is authored by John D. Hood, Mark Bednarski, Ricardo Frausto, Samira Guccione, Ralph A. Reisfeld, Rong Xiang, and David A. Cheresh and appears in the June 28, 2002 issue of the journal Science. The research was supported by the National Institutes of Health and by a grant from Merck KGaA. *