Lighting Up the Inside of Cells

Cancer therapies without side effects may come from X. Nancy Xu’s nanoparticle probes of living cells

By Jim Raper

X. Nancy Xu, associate professor of chemistry and biochemistry at Old Dominion University, won a $1.25 million grant from the National Institutes of Health (NIH) in 2006 that underscored her growing international reputation in nanobiotechnology.

In the summer of 2005 she had received a $1.3 million award from the National Science Foundation for fundamental cellular studies at the nanoscale, which ranges from one-billionth to one-millionth of a meter.

Less than a year later, the NIH chose Xu (pronounced “shoo”) to do single-cell and nano-probe research that sometime in the not too distant future could lead to more efficient cancer therapies and to other revolutionary medical procedures that treat diseases without causing adverse side effects.

The young scientist’s reputation received another boost about the same time the NIH R01 grant was announced, when her work was highlighted in a National Cancer Institute (NCI) article (http://nano.cancer.gov/news_center/monthly_feature_2006_may.asp). Prepared by the NCI Alliance for Nanotechnology in Cancer, the article is titled “Mission to the Inside of a Living Cell” and it emphasizes the advances in cancer research made possible by nanotechniques Xu and her research group have developed for probes of living cells. Most past and current research findings about biochemical reactions in cells come from experiments with dead cells or with purified biomolecules extracted from cells. The “rate of a biochemical reaction occurring in a test tube could be quite different from that observed for the same reaction inside a cell,” the article states.

In recent years, Xu and her research group at ODU have been creating nanoparticles that can enter a cell and literally “light up” the interior. The NCI article gives high marks to her silver nanoparticles, which are exceedingly bright and do not photo-decompose, surpassing any other available probes for cellular imaging.

Cancer research inside cells
These silver nanoparticles, according to the article, promise to provide detailed information via advanced microscopes about the biological processes and dynamics in living cells. This information can be used to (1) identify changes that occur when cells undergo malignant transformation, (2) perform single-cell cancer tests, and (3) provide exceedingly early cancer detection that could bring major improvements to cancer therapies.

“The primary challenge now is to develop methods for modifying the surface of the nanoparticles to make them more biocompatible, so that more biological processes can be observed without perturbing or destroying the cell’s intrinsic biochemical machinery,” Xu is quoted as saying in the NCI article.

“That is exactly what we are doing now,” she said in an interview in early 2007.

On the ODU campus, Xu’s successes in the cutting-edge research often have been cited as evidence of progress in the university’s quest to be a Top 100 research institution.

“She is a very gifted and talented scientist who has demonstrated an extraordinary ability to garner the sort of high-level, competed funding that raises the national stature of a research university,” said Richard V. Gregory, former dean of ODU’s College of Sciences and current chair of the Department of Chemistry and Biochemistry.

“Because of this type of funding, ODU is being recognized as an emerging leader in nanoscience, and we look forward to continued growth in the field under the leadership of Nancy and her colleagues,” Gregory added.

Xu said she is especially pleased with the award, given the recent NIH budget paring. “This is a confirmation of the importance of our research program, and I certainly look forward to getting more exciting research projects done. I am extremely proud of my past and present students and postdocs for their significant contributions to the research program. We share the common goal of advancing scientific research, and we all work very hard to achieve our goal,” she said.

Collaborators are at ODU and in France
The NIH award, which provides research funding over five years, will allow extensive nanoparticle research by Xu and her two chief collaborators, Christopher Osgood, ODU associate professor of biological sciences, and Jean-Michel Jault, a researcher at France’s Commissariat a l’Energie Atomique. The researchers will develop optimal nanoparticle probes to study the molecular mechanism of a transporter that is primarily responsible for multi-drug resistance in cancer therapy. The research also will involve the use of nanoparticles as carriers for effective drug delivery.

Osgood, a veteran researcher who has worked with Xu on previous projects, is quick to praise the Chinese-born scientist. “She is nearly unique in having simultaneous support from both NSF and NIH,” he said. “Both funding agencies are typically supporting the top 5-10 percent of applications. To receive million-dollar awards from both is a spectacular achievement and an indication of the high regard for Dr. Xu’s work and her research team.”

The research will focus on ATP-binding cassette (ABC) transporters that are present in bacteria cells, as well as in human cells. These 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 molecules of 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.

With more study, the day may come when chemotherapies, for example, 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.

Better knowledge of intracellular activity also may bring preventive therapies in which drugs are introduced into cells to guard against disease.

Nanoscale research to play vital role
Xu said that she foresees “profound” advances in medicine and many other fields based upon nanoscience and nanotechnology. “It is truly interdisciplinary. Every scientist and engineer can make significant contributions to his or her own field using nanoscience and nanotechnology. There is no doubt that nanoscience and nanotechnology will play a vital role in advancing every scientific discipline and major breakthroughs will take place in this exciting, emerging new field.”

She said she believes any university that aspires to be recognized as a research institution in the U.S. must choose nanoscience and nanotechnology as a major research focus. “It is crystal clear that no institution can become a leader in science and engineering without a distinguished nano program,” she insisted.

Through her research projects and several grants, Xu has become known on the ODU campus as a standard-bearer for nanoscience and nanotechnology. She has published and presented research papers, chaired symposia at conferences throughout the world and recently authored a book titled “New Frontiers in Ultrasensitive Bioanalysis: Advanced Analytical Chemistry Applications in Nanobiotechnology, Single Molecule Detection and Single Cell Analysis” (Wiley-Interscience).

Her dream is to help grow nano-research at ODU to the point that its various projects are integrated into one initiative and conducted under the auspices of one discrete, well-funded center and in a state-of-the-art nano-facility. She already has her eye on advanced instrumentation, such as a $2 million high-resolution transmission electron microscope and $1 million nano-fabrication apparatus, which she needs for her ever more sophisticated analysis.

“To make this dream come true, it will require substantial institution support, and I certainly cannot do it alone,” she said.

Currently, she is able to use the services of most of the advanced nano-facilities around the nation for her research program via National Nanotechnology Infrastructure Network (http://www.nnin.org/).

Xu is the sole principal investigator on the NIH award. She sees the award as an indicator of her passage from young investigator to established investigator. As a young investigator, she said, one might get “favored considerations.” For this NIH R01 grant, however, she had to compete alone, and without special considerations, against a full field of seasoned investigators through the most rigorous review process conducted by a NIH panel of 20-30 experts in the field.