Grant to Xu Opens New Vistas for Her Nanobiotechnology Research
The National Institutes of Health (NIH) has awarded Old Dominion University nanobiotechnology researcher X. Nancy Xu nearly $500,000 of American Recovery and Reinvestment Act funds to advance her studies involving nanoparticle probes of cells for better understanding of multidrug resistance.
Xu, professor of chemistry and biochemistry, is currently working under a $1.3 million NIH grant that she received in 2006 and has supported her groundbreaking research into the creation and utilization of nanoparticles for biological applications. These nanoparticles can enter living cells and embryos in order to accomplish specific missions.
One goal of the work has been to learn more about the mechanism by which cells expel foreign objects. This process can frustrate nanoparticle probes of cellular functions or deliveries of medicine into cells.
The new grant will make it possible for Xu and her research team to use advanced cryo- electron microscopes and other instrumentation at the National Center for Macromolecular Imaging (NCMI) at Baylor University's College of Medicine in Houston. The title of the grant, which comes via the NIH's National Institute of General Medical Sciences, is "Nanoassay for Realtime Molecular Probing ABC Transporter." The project period is Sept. 30, 2009, through April 2011.
"This support gives us access to state-of-the-art instrumentation at NCMI and enables us to study the structure, at atomic resolution, of the membrane transporter that leads to multi-drug resistance," Xu said. "The study of the structure of membrane transporters at atomic spatial resolution will be used to compare with our real-time dynamics study of individual membrane transporter using single nanoparticles at millisecond temporal resolution, aiming to illustrate the comprehensive functions of membrane transporters that are responsible for multidrug resistance."
She said the outcomes of this study will aid the design of more effective therapies to treat a wide variety of diseases, such as cancer.
ABC (ATP-binding cassette) transporters are membrane proteins that serve, in layman's terms, as gatekeepers and bouncers for cells. Of particular importance to medical science is the transport mechanism by which intruding specks-such as nanoparticle probes or antibiotics and cancer-fighting medicine-are recognized and expelled from cells. Although the transport mechanism is a natural protective measure, it works against physicians trying to eliminate sick cells. It "bounces" probes or medicines that are sent into cells to arrest an infection or malignant growth of tumors.
Xu said that she is fascinated by such a mechanism-also called an efflux pump-that can be carried out at the molecular level. "No human is able to make such a smart pump that can recognize and extrude any harmful substances, ranging from therapeutic drugs to dyes and nanoparticles. How does the pump do this?"
With more study, the day may come when chemotherapies could have stealth qualities. Molecules of medicine would be able to enter cells and avoid the ABC transporters long enough to perform their mission. This would allow precise targeting of cancer cells and avoid the current massive doses of medicines needed to outgun the transporters. The massive doses kill healthy as well as diseased cells and are what cause the sicknesses and severe symptoms that accompany chemotherapy, the so-called side effects.
The NCMI in Houston has among its array of instruments four electron cryomicroscopes. This is an advanced type of transmission electron microscope (TEM) that has a specimen holder capable of maintaining the specimen at very low temperatures in liquid nitrogen or liquid helium. This allows for specimens that are prepared in vitreous ice, the preferred preparation technique for imaging individual molecules or macromolecular assemblies.
Xu's work, which also received $1.2 million in funding in 2005 from the National Science Foundation, explores fundamental questions posed by nanobiotechnology.
In research reported over the past two years, the Xu research group at ODU has been able to create smaller and smaller silver and gold nanoparticles that can be used as biosensors to study molecular-level functions, such as of molecular machinery of individual key proteins inside live cells. The proteins mediate a variety of biological effects, such as immune regulation, antitumor activity and infection resistance.
Also reported have been new ways to synthesize stable nanoparticles that are particularly well suited for complex probes of live zebrafish embryos. These new monodisperse-or size-consistent-nanoparticles remain stable (non-aggregated) in solution for months, and they do not photobleach under white light illumination. The researchers have been able to deploy these tiny probes to simultaneously image multiple nanoenvironments of live cells and zebrafish embryos in real time.
Photostable single-nanoparticle photonics and the single-nanoparticle imaging system developed by the Xu group enable the direct characterization of size and location of nanoparticles inside cells and embryos in real-time.
Another accomplishment of the Xu group has been the development of an in vivo system-using zebrafish embryos-to screen the biocompatibility and toxicity of nanomaterials.
In 2007 and 2008, Xu won Nano 50 Awards from Nanotech Briefs, the digital newsletter from the publishers of NASA Tech Briefs. The annual awards program honors the top 50 technologies, products and innovators that have significantly impacted, or are expected to impact, the state of the art in nanotechnology. A panel of experts in nanotechnology and micro-electromechanical systems selected the winners.
The 2007 award was for advances in technology. In 2008, the award was in the innovator category.
Xu was named in a 2006 article prepared by the National Cancer Institute as a pioneering developer of nanotechnology that can be used in the war against cancer. The article, titled "Mission to the Inside of a Living Cell," noted the benefits of studying biochemical reactions inside live cells, rather than dead cells. Similar studies in the past were conducted with dead cells or purified biomolecules extracted from cells.