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Left to right:James Lee, PhD, professor and director of the National Science Foundation Center for Affordable Nanoengineering of Polymeric Biomedical Devices at Ohio State; Chenquang Zhou, PhD candidate, Pharmaceutics; John Lanutti, PhD, professor of Engineering; Robert Lee, PhD, professor of Pharmacy; Kris Jantana, MD, assistant professor of Otolaryngology – Head and Neck Surgery; Jeffery Chalmers, PhD, professor of Chemical and Biomolecular Engineering and Mariano Viapiano, PhD, assistant professor of Neurological Surgery.

By Bob Hecker
Photography by Roman Sapecki

Researchers in several colleges at The Ohio State University are teaming up to apply nanotechnology to improve the detection and treatment of cancer.

"Nanotechnology offers a new tool for more effective cancer detection techniques and treatment," says James Lee, PhD, the Helen C. Kurtz Professor of Chemical and Biomolecular Engineering and director of the National Science Foundation (NSF) Center for Affordable Nanoengineering of Polymeric Biomedical Devices at Ohio State.

"Through nanotechnology, we can make multifunctional materials and devices for detecting, diagnosing and perhaps treating cancer by delivering therapeutic genetic material into cells with minimal toxicity," says Lee, who also is a member of Ohio State's Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James).

Nanotechnology enables scientists to create products with new structural attributes by engineering their molecular features, a process that involves working at or around the scale of a nanometer, or one billionth of a meter. "The products themselves don't have to be on the nano scale, but they have an altered nanostructure that gives them special characteristics," Lee explains.

Ohio State's Nanoengineering Center is one of 19 Nanoscale Science and Engineering Centers funded by the NSF. It is the only one that solely develops polymer-based bionanotechnology, or creating soft materials primarily for medical use. Lee says softness is important for biocompatibility in working with tissue and proteins.

"Ohio has always been strong in the polymer industry—automotive and aerospace are examples—and we have a strong University workforce at Ohio State, where we're training the next generation of researchers in the polymer field," he adds. "We took advantage of this when we applied for our NSF grant by proposing to apply polymer-based nanotechnology to the medical field."

A five-year, $12.9 million NSF grant established the Center in 2004. The grant was renewed in 2009 for another five years at $12.5 million. The Center comprises approximately 25 Ohio State faculty, mainly from the colleges of Engineering, Arts and Sciences, and Pharmacy, who are collaborating with scientists and physicians in the College of Medicine and the OSUCCC – James on some 20 joint projects. The Center also has a medical advisory and evaluation board consisting of physicians and researchers from the College.

In addition, the Center works with seven partner institutions: Duke University, University of Illinois at Urbana-Champaign, University of Michigan, Massachusetts Institute of Technology, Oakwood University, University of California at San Francisco, and State University of New York at Albany.

The Center's research vision is aggressive: to revolutionize medical diagnosis and treatment by developing affordable, environmentally and biologically benign nanoengineering techniques that use polymers, biomolecules and nanoparticles to design and produce biomedical and therapeutic devices.

In its first five years, the Center yielded more than a dozen patents and nine commercial spin-off companies. Among its developments were polymer scaffolds that support the growth of blood vessels for transplant, techniques for shaping DNA into structures that might form sensors for biological agents, and a compact disk that contains tiny channels that transport fluids for medical testing.

Now the Center is integrating its nanomaterials and technologies into sophisticated drug- and gene-delivery methods, and into cell-sorting and analysis techniques to promote personalized health care, Lee says.

The ultimate goal, he adds, is to build a nanofactory that integrates nanofluidic circuits and synthetic chemistry into continuous production of nanostructures and devices for treating cancers, chronic infections and central nervous system diseases, as well as expediting vaccine delivery.

"Our proposed nanofactory will combine several technologies to do things more powerfully and efficiently, possibly leading to breakthroughs," Lee says.

Here's a look at three promising cancer studies at Ohio State that involve collaborative work in nanotechnology.

MIMICKING MALIGNANT MIGRATION
Cancer researchers investigating how malignant brain tumor cells migrate into surrounding tissue have worked with engineers at the Center to develop biocompatible nanofibers that mimic the neural topography used by migratory cells during metastasis.

Mariano Viapiano, PhD, a researcher at the OSUCCC – James, says growing tumor cells on nanofibers instead of in petri dishes produces behavior that more closely mimics the behavior of cells in actual tumors.

Viapiano and John Lannutti, PhD, of the College of Engineering, have been leading collaborators on this project for more than two years. Lannutti heads the design of nanofibers—which can be observed only through a scanning electron microscope—and Viapiano studies the behavior of cells cultured in these fibrous molecular scaffolds and their response to novel drugs.

Nanofiber Solutions, a company formed by Lannutti and his student, Jed Johnson, is marketing these nanofibers commercially and has received NIH and NSF small-business funding to aid in the transition to market.

"Dr. Lannutti has investigated an impressive number of chemical compound combinations and physical processes to make fiber scaffolds that increasingly resemble the texture of the brain," Viapiano says. "My lab designs methods to analyze cell motility, performs biochemical and genetic analyses of the cells, and tests experimental compounds that could be anti-invasive in vivo."

He explains that cells cultured on petri dishes must adapt to a homogenous, rigid surface that alters their migratory mechanisms.

"But by providing the cells with an elastic 3D scaffold with complex topography, we challenge them with physical conditions that more closely resemble the natural tissue environment," Viapiano says.

He notes that some drugs known to inhibit cell migration in brain tissue are ineffective when the same cells are cultured on petri dishes, but the drugs are effective again when the cells are cultured on nanofibers.

Viapiano says researchers have learned from this new model of cell culture that they can reproduce, at least in part, complex mechanisms of migration using a controllable in vitro model that allows them to perform analyses not possible with tissue samples.

"Our next steps are to increase the throughput of this model to perform comparative studies in cultured cells and eventually in fresh biopsy samples," he says. "The ultimate benefit will be having a reproducible culture environment that can be used for basic research and as a potential bioassay for clinical applications."

DETECTING CTCs
Bioengineers and cancer specialists have produced a blood test that uses nanotechnology to reveal circulating tumor cells (CTCs) and thus determine the aggressiveness of squamous cell carcinoma of the head and neck (SCCHN).

Jeffrey Chalmers, PhD, a professor of Chemical and Biomolecular Engineering and a researcher at the OSUCCC – James, where he directs the Analytical Cytometry Shared Resource, says the technology, which was developed at Ohio State and the Cleveland Clinic Foundation, is a negative depletion process that uses magnetic nanoparticles to isolate and quantify CTCs from the blood of patients with SCCHN.

Reporting in the Journal of the American Medical Association's subspecialty journal, Archives of Otolaryngology – Head and Neck Surgery, the researchers identify three general CTC detection methods: immunocytochemistry, which implies visual observations; flow cytometry or image cytometry; and reverse transcriptase polymerase chain reaction. Using a negative depletion technique before employing one of these methods can greatly increase the sensitivity and specificity of detection, the authors say.

"Our negative depletion process enriches for CTCs from human blood by removing normal blood cells using immunomagnetic separation," Chalmers explains, noting that the technology is being commercialized by a local company.

In a study of 48 patients with SCCHN who were undergoing surgery, the investigators determined that, when they used this technique, their patients who were found to have no CTCs had a statistically significant improved disease-free survival. A blood test with such a prognostic capability could have important clinical implications, the scientists say.

"With prospective clinical follow-up now as far out as three years after surgery, we have seen correlations suggesting that the presence of these cells in the blood may be related to a worse outcome," says Kris Jatana, MD, an assistant professor in the Department of Otolaryngology – Head and Neck Surgery who has been involved in this work with SCCHN since its conception at the OSUCCC – James. Jatana was co-first author on the published manuscript. "This may help identify patients with more aggressive cancers and enable us to customize treatments accordingly. Our goal is to improve patient outcomes."

Jatana says there is still no standardized prognostic blood test for SCCHN, or even for cancer surveillance, although many experimental techniques have been described.

"We believe our technique is superior to others as it removes normal cells from the blood, allowing for the detection of any abnormal cells—the CTCs," he says. "Many techniques done throughout the United States and internationally identify only cells with a specific surface marker, which creates an intrinsic bias and the potential to miss abnormal cells."

Jatana finds their work extremely exciting. "With continued investigation we hope to further characterize these cells and determine if this technology can also be used in surveillance for the earliest detection of microscopic cancer recurrence."

DYNAMIC DELIVERY
One problem with using viral vectors for gene therapy is that some viruses generate immune responses that complicate or hinder the treatment. Scientists are thus pursuing nonviral vector techniques as well.

At Ohio State, researchers have designed nanoparticles that appear to deliver genetic material into cells with minimal toxicity. In laboratory studies, the researchers found that this vector can deliver DNA deeply enough into a cell to allow activation of its passenger gene.

Made of calcium phosphate in a lipid shell, the biocompatible nano-particle protects DNA on its journey into the target cell and then dissolves via complex chemical reactions.

This research, published in the International Journal of Pharmaceutics, involves scientists from the colleges of Engineering, Pharmacy and Medicine, several of whom are affiliated with the Nanotechnology Center, including its director James Lee and colleague Robert Lee, PhD, a professor in the College of Pharmacy who is a member of the OSUCCC – James and an expert in targeted nanoparticle and liposomal drug-delivery systems.

First author Chenguang Zhou, a PhD candidate in Pharmaceutics, notes that other attempts to use liposomes as nonviral vectors for gene therapy have protected the passenger DNA but have not adequately released the material into the cell.

"While calcium phosphate has been used to deliver plasmid DNA for decades, the method is typically characterized by low and irreproducible transfection efficiency," Zhou says. "But our novel lipid-coated nano-calcium phosphate vector provides consistently efficient and satisfactory delivery. This superior stability makes our vector a promising candidate for clinically useful gene delivery."

The team next plans to test the nanoparticle's ability to travel through the bloodstream and enter target cells in animals.

"We need to study how the vector maintains its integrity and protects the plasma DNA in the bloodstream. We also must learn how to avoid the unwanted internalization of the vector by immune cells," Zhou says. "Then we may want to add targeting moieties that increase the binding and internalization of the vector to the target cells."

When the experimental vector does reach the clinic, Zhou speculates that it may be first applied in patients with leukemias or liver cancer.

COLLABORATIONS CONTINUE
"Our Center so far has developed a number of gene/drug delivery vectors," Zhou says. "We keep close collaboration with oncologists at the OSUCCC – James to understand the clinical demand for gene therapy and to test our vectors in clinically relevant animal models. We also work with pharmaceutical companies for evaluating our formulations in clinical settings."

"Nanotechnology allows us to achieve a degree of refinement and control in analyzing biological processes that would've been unthinkable 10 years ago," adds Mario Viapiano, referring not only to his team's brain cancer studies but to malignant mechanisms in general. "Nanoparticle applications provide tools for specific targeting of tumors or for bioassays with
diagnostic potential, enhancing personalized medicine. This should make the technology very exciting for physicians and their patients."

"But none of this can be accomplished by one discipline alone," says Nanotechnology Center Director James Lee. "Our collective goal is to make a difference, and collaboration is the key."

 
6-Jan-11
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