Angiogenesis, the growth of new blood vessels, plays a critical role in several chronic human diseases, including metastatic cancer. In fact, several new anticancer therapies are designed to starve tumors by shutting down angiogenesis, but the lack of a good assay for quantifying angiogenesis in the body has hampered the development of effective antiangiogenesis therapies.
Late fall 2008, researchers at The Siteman Center of Cancer Nanotechnology Excellence described a novel nanoparticle capable of imaging angiogenesis using magnetic resonance imaging (click here to see earlier story). Now, researchers at the University of California, Berkeley, have developed a second type of nanoparticle that can image angiogenesis using positron emission tomography (PET). The investigators, led by Jean Fréchet, Ph.D., describe their new nanoparticle in a paper published in the journal Proceedings of the National Academy of Sciences of the United States of America.
The investigators used a nanoparticle known as a dendrimer, a spherical polymer with multiple chemical functionality built into its structure. This chemical functionality enabled the investigators to incorporate radioactive bromine-76 into the core of the dendrimer and add a targeting agent to the outside of the dendrimer. For a targeting agent, the researchers used cyclic-RGD, a well-studied peptide that binds strongly to the integrin avb3, a protein expressed only on the surface of new blood vessels. The dendrimer itself was designed to degrade in the body once imaging is complete.
Studies using cells grown in culture showed that cells expressing avb3 readily took up the targeted dendrimers, whereas other cells did not. These experiments also showed that binding affinity for the targeted nanoparticle was some fiftyfold higher than for cyclic-RGD alone. This significant boost in binding affinity likely results from a Velcro®-like effect in which multiple cyclic-RGD molecules on the nanoparticle bind simultaneously to multiple avb3 molecules on the surface of target cells. Subsequent studies in mice showed that the targeted dendrimer was able to image sites of angiogenesis with relatively little background from nonspecific binding.
This work is detailed in the paper “Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis.” Investigators from Washington University in St. Louis also participated in this study. An abstract of this paper is available at the journal’s Web site.