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 enables 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 latest issue of the journal Science, the TSRI investigators combined a gene that shuts off angiogenesis with a 50-100 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.
This anti-cancer nanoparticle is like 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 all the supply routes to destroy the tumor. Once angiogenesis is stopped, the tumor cells starve, and the tumor is ultimately destroyed.
Anti-angiogenics have been known of 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 TSRI Immunology Professor David Cheresh, Ph.D., who led the study.
In the current study, the TSRI 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).
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. Everywhere 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, and thereby 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 (age-related macular degeneration) and in patients with diabetes (diabetic retinopathy).
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.