Gene delivery by vector that targets neovasculature destroys tumors
Last Updated: 2002-06-27 14:00:36 -0400 (Reuters Health)
By Karla Gale
NEW YORK (Reuters Health) - A new type of nonviral vector can deliver genes specifically to endothelial cells of angiogenic blood vessels. According to a report in the June 28th issue of Science, coupling this vector to a mutant Raf gene and injecting it into mice causes apoptosis of tumor-associated endothelium and sustained regression of established primary and metastatic tumors.
"The combination of gene delivery and targeting of the appropriate cell type gives us the success we're seeing," co-author Dr. David A. Cheresh told Reuters Health.
Integrin-alpha-v beta-3, an endothelial cell receptor, potentiates tumor cell invasion and proliferation, report Dr. Cheresh, of The Scripps Research Institute in La Jolla, California, and colleagues. They note that this protein also promotes internalization of several pathogenic viruses.
Based on those characteristics, they synthesized a cationic polymerized lipid-based particle to which they coupled an alpha-v beta-3-binding ligand. The particles were between 40 nm and 50 nm in diameter and were stable for months.
After demonstrating that the particles could selectively deliver genes to angiogenic tumor-associated blood vessels, the researchers complexed particles with a mutant Raf gene that blocks endothelial signaling and angiogenesis in response to growth factors. They first targeted the gene to melanomas that intrinsically lack the alpha-v beta-3 receptor.
Three days after injecting the gene-vector particle into mice with established melanomas, microscopic examination showed apoptosis among the new blood vessels and in rings of tumor cells surrounding the affected vessels. After 6 days, there was 95% to 100% tumor regression, which was sustained for more than 250 days.
According to the California-based investigators, these results suggest that "the antitumor effect is based on the antiangiogenic effects, not a direct effect on the tumor." Further experiments showed the therapy was also effective against established pulmonary and hepatic metastases of colon carcinoma.
Dr. Cheresh and his associates point out that the lipid-based nanoparticles are not as immunogenic as viral vectors. Therefore, they surmise, "it may be feasible to deliver therapeutic genes repeatedly to angiogenic blood vessels for sustained treatment of diseases that depend on angiogenesis and vascular remodeling."
"The interesting thing is that raf kinase plays a central role in multiple mechanisms of angiogenesis, so it doesn't matter where new blood vessel growth is stimulated--we can turn it off," Dr. Cheresh said in an interview. For example, he said, they have observed efficacy using this approach in models of rheumatoid arthritis and inflammatory ocular disease.
Dr. Cheresh said that the nanoparticle vector has not been tested in humans, but "the integrin-alpha-v beta-3 receptor is not widely expressed on much of anything except angiogenic endothelium," so it is likely to prove safe. He added that he and his associates have observed no signs of toxicity in animals.
Science 2002;296:2404-2407. |
