News Release

Fluorescent Viral Nanoparticles Permit High Resolution In Vivo Vascular Imaging

New Biological Imaging Agent Shows Distinct Advantages Over Current Particles

LA JOLLA, CA, February 27, 2006—Scientists at The Scripps Research Institute have shown that cowpea mosaic virus (CPMV) can be used as an "exceptionally bright" imaging agent that permits high resolution in vivo visualization of the vascular endothelium, the cells that line the inside of blood vessels, for as long as 72 hours. These results strongly suggest that fluorescently dyed CPMV nanoparticles could become a "powerful tool" to image tissues deep inside living organisms in the laboratory and, potentially, in a clinical setting as well.

The study was published in the March issue, Volume 12, Number 3 issue of journal Nature Medicine. An online version appeared on the journal's Web site February 26, 2006.

The researchers were able to use the nanoparticles, densely coated with fluorescent dye, to image the vasculature and blood flow in living mouse and chick embryos to a depth of up to 500 micrometers. The researchers also mapped human tumor angiogenesis, further demonstrating the effectiveness of fluorescent CPMV as a non-invasive platform to identify blood vessels and monitor the neovascularization of the tumor microenvironment.

The lead author of the study, John D. Lewis, a postdoctoral fellow at the Scripps Research Department of Cell Biology and the Division of Vascular Biology, said: "Notwithstanding the technical challenges, intravital microscopy offers a view into the complex interplay of multiple cell types, signals and blood flow that cannot be adequately duplicated in a petri dish. Our study shows that CPMV-based imaging agents can be an extremely useful tool in a currently sparse toolbox for the visualization of blood vessels for long periods of time."

An inert but highly compatible biological compound like CPMV has a number of distinct advantages over currently available particles, according to the study. CPMV particles can withstand a variety of solvents and extremes of temperature and pH levels while maintaining structural integrity. The virus's most important advantage, however, is the fact that it is both biocompatible and multivalent. The CPMV has 300 different surface attachment sites, which, the researchers noted, "makes [it] an ideal in vivo imaging agent."

In the study—a collaborative effort between the Scripps Research laboratories of Heidi Stuhlmann, Marianne Manchester, and James Quigley—researchers injected embryos with fluorescent CPMV and found that the brightly decorated virus nanoparticles remained internalized by the vascular endothelial cells of the embryos over a period of several days. The same was true when CPMV was injected into adult mice. In both cases, the images produced using CPMV were "superior to similar-sized fluorescent nanospheres for the resolution of microvasculature during…imaging," the researchers reported.

The researchers also experimented with PEG (polyethylene glycol) coated CPMV, which is known to minimize molecular interactions and increase the half-life of blood-borne agents. The PEG coating completely inhibited the internalization of CPMV in chick embryo endothelial cells in vivo. A tissue section analysis showed that coated CPMV particles were located exclusively in the blood stream. These results suggest that PEG coated CPMV could be particularly useful in the visualization of blood volume and blood flow in vivo.

In another experiment, chick embryos bearing highly vascularized human tumors were injected with CPMV and visualized by epifluorescence microscopy over a period of three days. The dye-labeled CPMV circulated freely throughout the tumor vasculature, entering and exiting the tumor as well as the capillary network within the tumor mass, the study noted.

"Our study shows that CPMV nanoparticles are well suited to the visualization of rare molecular targets," Lewis said, "and the use of advanced imaging technologies will enhance the quality at even greater tissue depths. CPMV is not limited to fluorescent labeling, so their multivalent properties can be exploited to display a wide variety of molecular tags, including radioactive isotopes, magnetic resonance imaging (MRI) contrast agents, specific enzymatic segments, or any combination of those. Because virus particles can be manipulated genetically, the door is wide open to future targeted molecular bioimaging studies."

Other authors of the study included Giuseppe Destito, of Scripps Research and the Dipartimento di Medicina Sperimentale e Clinica, Universitá degli Studi Magna Graecia di Catanzaro, Viale Europa, Campus Universitario di Germaneto, Catanzaro, Italy, and the following scientists from Scripps Research: Andries Zijlstra, Maria Gonzalez, James P Quigley, Marianne Manchester, Department of Cell Biology, and Heidi Stuhlmann.

This study was supported by the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute, headquartered in La Jolla, California, in 18 buildings on 40 acres overlooking the Pacific Ocean, is one of the world's largest independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel.

Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical research facility, will be built in Palm Beach County. The facility will focus on basic biomedical science, drug discovery, and technology development. Palm Beach County and the State of Florida have provided start-up economic packages for development, building, staffing, and equipping the campus. Scripps Florida now operates with approximately 160 scientists, technicians, and administrative staff at 40,000 square-foot lab facilities on the Florida Atlantic University campus in Jupiter.

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