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Nanoscale Cover Article Highlights Work of Xu, Huang, Browning

The research group of X. Nancy Xu, Old Dominion University professor of chemistry and biochemistry, reports in Nanoscale, the journal of The Royal Society of Chemistry based in Great Britain, that the group's proprietary nanoparticle biosensors and single-molecule imaging techniques are now able to spy on cellular signaling pathways that are tied to diseases such as cancer.

Just last summer, Xu and Tao Huang, an ODU research scientist who works with her, wrote a Nanoscale cover story about their development of a photostable optical nanoscopy technique, which they call PHOTON.

This far-field optical microscopy technique, when used in concert with the Xu group's single-molecule nanoparticle optical biosensors (SMNOBS), have enabled the team to map individual molecules and their binding with receptors on live cells in real time. These molecules - called ligands - can influence the functions of the cells they bind with. Precise information about the distribution and number of receptors on single live cells is needed for the creation of more effective disease therapies.

In the latest article, Xu, Huang and Lauren Browning, a Ph.D. student who works with the Xu group, report that they have been able to use PHOTON and SMNOBS to follow signaling pathways from the exterior membrane to the interior of the cell, and with exceptionally sharp resolution. Of specific interest to them are single-molecule ligands called tumor necrosis factor-alpha (TNF-Alpha), which can bring about inflammation, fever and even the demise of the cells they bind with. Apoptosis is the orderly death of a cell that can come from a cascade of functions triggered by TNF-Alpha.

This ligand is especially important because apoptosis can fight cancer. Unregulated apoptosis, of course, is not good; for example, it can result in atrophied body parts. But on the other hand, tumors can grow, sometimes remarkably fast, where apoptosis is inhibited. So knowing how apoptosis is signaled - or is not signaled - and revealing exactly how a cascade has to flow in order to bring about this orderly cell death is of paramount interest to scientists searching for a variety of therapies for human diseases.

"This study provides new insights into complex real-time dynamic cascades and molecular mechanisms of apoptotic signaling pathways of single live cells," the researchers write in their latest article, which has been published on the Nanoscale website and is soon to be published as the cover article in the print journal. "PHOTON provides superior imaging and sensing capabilities and SMNOBS offer unrivaled biocompatibility and photostability, which enable probing of signaling pathways of single live cells in real time at single molecule and nanometer resolutions."

So far, the researchers have found a correlation between the onset of apoptosis and the way TNF-Alpha molecules and their receptors can bind and diffuse as clusters on the exterior of a cell. "Notably, the sizes of the clusters play more significant roles in initiating cellular apoptosis than their numbers," they write.

"The results suggest the possibility of tuning and inhibiting signaling pathways by controlling formation of single ligand-receptor complexes and their clusters."

Ligand-receptor binding and cellular signaling happen at the nanoscale - between one-billionth and one-millionth of a meter - and are very difficult for researchers to map.

One of the drawbacks of existing nanoscopy techniques can be the use of laser light as an excitation source. This often is toxic to cells and organisms that are being probed. That's where PHOTON can help. This far-field optical microscopy technique, used in concert with SMNOBS, enables the ODU researchers to map individual ligand molecules and their binding with their receptors (single protein-ligand complexes) in real time at nanometer scale.

PHOTON uses a new-generation sub-diffraction imaging nanoscope based on a standard far-field optical microscope equipped with a multispectral imaging system. The illumination source is a standing microscopic white-light illuminator (100-watt halogen lamp). No laser excitation source is needed.

Over the past decade, the Xu research group in nanobiotechnology has looked into a possible "stealth" quality for single-nanoparticle probes of living cells or for similar nanoparticle vehicles that can deliver medicine into the cells. In other words, they have been studying means by which nanoparticles can penetrate cells and accomplish their mission without harming the cells or being ejected by an efflux pumping mechanism that utilizes membrane transporters. This mechanism naturally targets foreign objects for ejection from cells.

The research group has reported success employing flecks of precious metals no longer than one-millionth of a meter as reliable probes of living cells and embryos. In this process, Xu and her colleagues have found ways to synthesize and purify silver and gold nanoparticles that will stay stable - one size, or monodisperse - over an extended period. They have also reported breakthroughs in the way they image and characterize nanoparticles using dark-field optical microscopy and spectroscopy.

The small size of the nanoparticles that have been created enables the specks to penetrate living organisms, but the surface area is large relative to the overall size, and this allows the particles to perform better in optical sensing and to carry a larger payload of drugs. The rainbow colors of these nanoparticles also contribute to their usefulness as probes and sensors.

Not only has the group's research advanced techniques for nanoparticle delivery of drugs, but also it has found that the nanoparticles alone, without a drug payload - particularly the large-size silver nanoparticles - may affect certain cellular functions. This means that the nanoparticles themselves could be used as nanomedicines, say, to kill cancer cells., as well as serving as probes to illustrate molecular pathways about how cancer occurs and explore more effective therapies.

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