Their study, published in the online early edition of The Proceedings of the National Academy of Sciences (PNAS) the week of Jan. 23 - 27, 2006, shows the use of biologically compatible materials to fabricate a "nanoshuttle" - thousands of times smaller than a human hair - which can be harnessed to viral particles to precisely home to disease wherever it hides.
Once there, the nanoshuttle can perform a variety of functions. The study defines how assembled particles of gold - a metal that is not rejected by the body - could possibly be "tuned" to destroy tissue or emit signals that can be detected by imaging devices. The system also can be adapted to form a flexible scaffold that can carry drugs, genes or even cradle restorative stem cells.
"Gold is a perfect metal to perform these different functions, and scientists have been trying to find a way to target such particles to specific organs or tissues, but it has been extremely difficult," says the co-leader of the study, Renata Pasqualini, Ph.D., professor of medicine and cancer biology. "Instead of taking the usual approach by using a synthetic molecule or polymer, we have found a way to mix a 'genetically programmable' nanoparticle with a biologically compatible metal that together target specific locations in the body."
For example, these nanoplatforms could potentially locate damaged areas on arteries that have been caused by heart disease, and then deliver stem cells to the site that can build new blood vessel tissue. To treat cancer, they also may be able to locate specific tumors by using an array of imaging techniques. The tumors could then be treated by either heating the gold particles with laser light and/or using the nanoparticles to selectively deliver a drug to destroy the cancer.
"Gold nanoshells and laser light have been tested in pre-clinical models previously, but it has been difficult to accurately target the therapy," says Wadih Arap, M.D., professor of medicine and cancer biology, co-leader on the study.
These nanoplatforms and scaffolds have not as yet been tested in vivo, but this study is the first to show how, in a laboratory, gold and phage (viruses that infect only bacteria) can combine and build a matrix that can support stem cells.
The disease-finding capability of these scaffolds is due to the specially engineered virus that displays a peptide that matches a protein receptor "zip code" on the tissue of interest. This homing technique was pioneered by the lead authors on the current study, Pasqualini and Arap. Their previous work revealed that the human vascular system contains unique molecular addresses, depending on the site of an organ or tissue, and that blood vessels also acquire abnormal signatures on diseased organs. They were the first to attach such unique vascular "zip codes" to phage, engineering them in such a way that these viral particles would go to these target addresses.
This advance was only made possible, Pasqualini says, because she and Arap invited chemist Glauco Souza, Ph.D., the paper's first author, to work on the problem.
"This was truly a multidisciplinary approach, and it brings together something chemists, physicists and biologists have been trying to do, separately and unsuccessfully, for a long time," Souza says.
"The beauty of this approach is that the phage can already be screened and selected to either target a certain cell type in the body, or home to certain tissues," Pasqualini says.
During their preliminary work, Souza discovered that certain properties of the capsid (the outer shell of the phage virus) would allow it to spontaneously assemble with gold particles.
"So if you can assemble gold particles onto the phage and incorporate a 'signature' molecule like imidazole, you immediately have an entity that is both a sensor, because it binds to a specific molecular signature, and a reporter, because it picks up specific properties of the gold which can be measured in a number of ways," Souza says.
The team also found that by manipulating solution conditions, the network of scaffolds would form a "hydrogel," a bio-inorganic environment capable of sustaining and nurturing stem cells. This biological matrix can potentially be used in two ways, according to Pasqualini and Arap. First, it could be used to grow needed tissue in a laboratory, which could then be delivered to patients. Alternatively, the matrix could be directly injected so that it can implant at the site of injury. There, the stem cells could potentially morph into tissue needed to internally repair the wound, the researchers say.
"This is our vision of the future, and, of course, it all needs to be further studied and translated into real clinical applications," Arap says. "But we can now think in those terms because of this pioneering work that merges the fields of vascular targeting and nanotechnology."
The study was funded by grants from the National Institutes of Health and by the Gillson-Longenbach Foundation.
In addition to Souza, Arap and Pasqualini, researchers who contributed to the study include, from M. D. Anderson: Dawn Christianson B.S., Fernanda Staquicini, Ph.D., and Michael Ozawa, B.S.; Evan Snyder from the Burnham Institute; Richard Sidman, M.D., from Harvard Medical School; and J. Houston Miller, Ph.D., from George Washington University.