NANO 10-9

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JUNIOR INVESTIGATORS GROW NANOMEDICINE PROGRAM

NANOMEDICINE RESEARCH GROWS AT UNMC

TRANSLATING RESEARCH IS NOT EASY

IN A FIELD THAT’S CONSTANTLY CHANGING, EDUCATION IS THE CONSTANT

INTERNATIONAL CONNECTIONS BUILD PROGRAM

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nano10-9 an annual publication of CDDN

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-9 COVER Artistic rendering of bacterial nanoparticles in the blood stream of the patient

JUNIOR INVESTIGATORS EXPAND NANOMEDICINE PROGRAM Eight junior investigators are using nanoparticles to find better ways to treat and cure stroke, hypertension, traumatic brain injury, obesity, Parkinson’s disease and cancer. They are part of an interdisciplinary team funded by a $10.6 million COBRE grant.

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14 NANOMEDICINE RESEARCH GROWS AT UNMC Congressional earmarks and grants from the National Institutes of Health support 32 faculty members who hold more than $34 million in federal research funding in the Center for Drug Delivery and Nanomedicine.

24 TRANSLATING RESEARCH IS NOT EASY An institute for translational nanomedicine is one of the goals of the CDDN. DEFUSING THE HYPERTENSION TIME BOMB

28 IN A FIELD THAT’S CONSTANTLY CHANGING, EDUCATION IS THE CONSTANT Important to any scientific field is the cultivation of new minds that one day expand that very field of research. Conferences, seminars and a certificate program serve those purposes.

32 INTERNATIONAL CONNECTIONS BUILD PROGRAM UNMC is extending its influence around the world through student and faculty exchange programs.

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10 CONTENTS

DRUGS DESIGNED TO “GO RAMBO” IN PANCREAS CANCER CELLS

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BIOIMAGING CORE LABORATORY PROVIDES CRITICAL SUPPORT

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NANOMATERIALS CORE LABORATORY PROVIDES NANOMATERIAL DEVELOPMENT AND CHARACTERIZATION

ROLE OF INFLAMMATION IS EXAMINED IN TRAUMATIC BRAIN INJURY RESEARCH

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NANOMEDICINE IS KEY TO NEW GENERATION OF DRUG DELIVERY Nano 10-9 is published once a year by the UNMC Center for Drug Delivery and Nanomedicine. Issues of the magazine can be found at cddn.unmc.edu. Permission is granted to reprint any written materials herein, provided proper credit is given. Direct all requests to Christine Allmon, callmon@unmc.edu., +1.402.559.9330 UNMC’s mission is to improve the health of Nebraska through premier educational programs, innovative research, the highest quality patient care and outreach to underserved populations.

Welcome to the first edition of Nano 10-9, which refers to the size of particles we work with — particles 100,000 times smaller than the head of a pin.

Full of promise and potential, nanomedicine is a rapidly growing field of research that may spark a new generation of therapies and diagnostic tools to combat human diseases.

By using nanoparticles, we can design and package drugs to be delivered directly to the site of disease or injury. This spares healthy tissue from collateral damage and the patient from unnecessary and harmful side effects.

UNMC became a leader in this field when, in 2004, it established the first academic center in nanomedicine in the United States. The Nebraska Center for Drug Delivery and Nanomedicine (CDDN) develops innovative tools for improving drug delivery systems through nanoscale technologies.

As director of the CDDN, I encourage the center’s 32 faculty members to take a multidisciplinary approach to each project and to think and design projects in terms of practical outcomes. Translational research is the key to progress and UNMC is uniquely poised to become an innovation accelerator that will be a boon to the economy of the state and country.

To achieve this transformative outcome we need to: • Establish a Biomedical Technology Incubator that attracts the best

researchers, entrepreneurs and capital from Nebraska and around the world to transfer our promising ideas into flourishing businesses; • Create the Technology Development Core Facility to provide resources and a research infrastructure that works with the incubator, pharmaceutical companies and granting agencies to advance innovation from the early stage to proof-of-concept; • Integrate and supplement UNMC’s new Biologics Production Facility with the resources for the manufacturing and characterization of therapeutic products for pre-clinical evaluation and clinical trials; and • Develop dedicated research facilities and space for new start-up companies and ventures in the biomedical technologies field.

This is an aggressive agenda, but the time is now to attract the best and the brightest scientists from around the world and become a creative powerhouse here in Nebraska. I hope you enjoy reading about the advancements we are making at UNMC.

Alexander V. Kabanov, Ph.D., D.Sc. Director, Center for Drug Delivery and Nanomedicine

UNMC is accredited by The Higher Learning Commission of the North Central Association of Colleges and Schools (HLC -NCA) and enjoys full accreditation of all its professional academic programs.

UNMC does not discriminate in its academic, employment or admissions programs and abides by all federal regulations pertaining to same.

Director of the Center for Drug Delivery and Nanomedicine: Alexander V. Kabanov, Ph.D., D.Sc. Writer: Elizabeth Kumru UNMC Public Relations Editor: Karen Burbach UNMC Public Relations Photography: Malone & Company Scott Dobry David Hussey Research Advisory Board: Thomas Rosenquist, Ph.D. Courtney Fletcher, Pharm. D. Dennis Robinson, Ph.D. Howard Gendelman, M.D. Kenneth Cowan, M.D., Ph.D. David H. Allen, Ph.D., P.E.

COBRE investigators. Front row: Alexander V. Kabanov, Ph.D., D.Sc.; Karen Gould, Ph.D.; and Larisa Poluektova, M.D., Ph.D. Back row: Xinming Liu, Ph.D.; Tatiana Bronich, Ph.D.; Michael Boska, Ph.D.; Elena Batrakova, Ph.D.; Matthew Zimmerman, Ph.D.; Jered Garrison, Ph.D.; Matthew Kelso, Pharm.D., Ph.D.

Junior investigators expand nanomedicine program Eight talented junior investigators at UNMC are using nanoparticles to find better ways to treat and cure stroke, hypertension, traumatic brain injury, obesity, Parkinson’s disease and cancer.

They are part of an interdisciplinary team funded by a $10.6 million COBRE (Centers of Biomedical Research Excellence) grant that was awarded in October 2008 to Alexander Kabanov, Ph.D., D.Sc. The five-year grant is a part of the Institutional Development Award (IDeA) program of the National Institutes of Health (NIH).

Dr. Kabanov, director of the Center for Drug Delivery and Nanomedicine and the COBRE Nebraska Center for Nanomedicine, also has used these tiny polymeric particles to build a worldclass nanomedicine facility at UNMC to develop novel drug delivery systems.

“The research projects funded by this grant will, one day, provide drug therapies to physicians that target disease without

harming the surrounding healthy tissue and spreading toxic side effects,” Dr. Kabanov said. “This will result in better clinical outcomes for patients.”

The grant is designed to help junior investigators jumpstart their careers in science.

“After one or two years, these investigators should be able to stand on their own with external funding based on the findings from these experiments,” he said.

Each junior investigator is paired with a mentor, including Dr. Kabanov, who also appointed an external advisory committee to review the annual progress of the projects. The committee may terminate the project if the researcher is not productive.

There are other benefits to having the COBRE grant.

“It allows us to attract the best and brightest scientists to Nebraska and develop novel technologies that contribute

to the economy of the state with the help of spin-off companies that bring the results of the scientific research to public use,” Dr. Kabanov said.

The COBRE is part of the Institutional Development Awards network created by the NIH/NCRR to more equally distribute funding to states that have not traditionally received as much funding.

The awards support multidisciplinary centers — each concentrating on one general area of research — that strengthen institutional biomedical research capability and enhance research infrastructure.

All five projects and the three seed projects focus on how polymer nano systems may be used to enhance the delivery of drugs, inhibit tumor growth and improve treatment of cancer, neurodegenerative and central nervous system-associated cardiovascular disorders, Dr. Kabanov said.

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Matthew Zimmerman, Ph.D.

DEFUSING the hypertension time bomb

One out of every four American adults is a walking time bomb.

High blood pressure or hypertension runs in the blood vessels of 75 million people over the age of 20 and leads to heart disease, the main cause of death for men and women in the United States.

Called the silent killer, hypertension develops over many years with no symptoms. Only after a bodily organ is irritated or damaged are the consequences of high blood pressure realized.

Although there are several drugs to treat hypertension, 20 percent of people with this disease are resistant to current therapy. No matter what they do, their blood pressure stays high, putting them at risk for stroke or kidney disease.

“One of the greatest scientific challenges for the improved treatment of brain-related diseases, such as hypertension, is developing therapies

that are able to penetrate cells in the brain called neurons,” said Matthew Zimmerman, Ph.D. Dr. Zimmerman works on a novel nanomedicine-based intervention for hypertension using a specially designed nanozyme to deliver a potentially therapeutic antioxidant protein — copper/zinc superoxide dismutase (CuZnSOD) — to neurons. This therapy also has the potential to help people with neurodegenerative diseases.

“We have shown that the CuZnSOD nanozyme is taken up by neurons and scavenges free radicals, or superoxide, in neurons stimulated with angiotensin II (AngII), a peptide involved in the development and progression of numerous cardiovascular diseases,” he said.

In neurons, AngII increases superoxide, which in turn mediates AngII-induced neuronal activation. Under

normal circumstances, the brain also produces superoxide dismutase (SOD), a scavenging enzyme that keeps the levels of superoxide in check.

Trouble comes when AngII levels in the body are chronically elevated as this leads to more superoxide production, which SOD may not be able to handle.

As a result, neurons in the brain are continuously activated and there is an increase in the sympathetic nervous system, which is known to play a key role in the pathogenesis of hypertension.

Dr. Zimmerman hypothesizes that the CuZnSOD nanozyme can enter neurons in regions of the brain that lack a bloodbrain barrier (BBB). These BBB deficient brain regions — named circumventricular organs (CVOs) — are known to control systemic cardiovascular function.

Recent experiments performed in collaboration with Irving Zucker, Ph.D., and Lie Gao, Ph.D., at UNMC, show

that a single intra-carotid injection of the CuZnSOD nanozyme stopped AngII from increasing blood pressure.

The results of this study, written by Dr. Zimmerman’s graduate student Erin Rosenbaugh, were published in the July 2010 issue of Biomaterials Journal.

Dr. Zimmerman has published 18 journal articles, six this year alone, with three more in the works. Originally from Wisconsin, he was recruited from the University of Iowa, Iowa City, in 2007.

Usually, when postdoctoral students are recruited, they’ve been doing research between two to five years and have independent funding.

Dr. Zimmerman had barely two years under his belt and only fellowship funding when he was noticed

by Dr. Zucker.

“I had an intuition that Matt would do well and he hit the ground running,” he said.

Since then, Dr. Zimmerman has become one of the better-funded junior investigators at UNMC. “Mentoring is an example you set for trainees,” Dr. Zucker said. “You want young people to go farther than you did.”

Dr. Zucker, one of UNMC Scientist Laureates, is a leading international figure in cardiovascular physiology. His team of scientists conducts groundbreaking heart failure research and is funded by a $6.1 million program project grant from the National Heart, Lung, and Blood Institute — a division of the National Institutes of Health. This grant has been awarded to him three times in succession since 1999.

He was awarded a $627,151 grant through the American Recovery and Reinvestment Act in 2009 to investigate the role statin drugs play in improved heart performance during heart failure. He also was recently awarded a subcontract through NIH to investigate the neural and vascular mechanisms that contribute to orthostatic hypotension.

Irving H. Zucker, Ph.D.

COBRE Project 2: A Nanozyme Antioxidant Therapy for the Treatment of Angiotensin II-dependent Hypertension Principal investigator: Matthew Zimmerman, Ph.D. Assistant Professor of Cellular and Integrative Physiology

Mentor: Irving H. Zucker, Ph.D. Professor and Chairman of the Cellular and Integrative Physiology Department

Grant: $222,750 for one year Dr. Zimmerman’s other grants: Mitochondrial Redox Systems in Neurogenic Hypertension Grant: $1,250,000 from July 2010 to June 2015 Funding agency: NIH Role: Principal investigator Role of Superoxide vs. Hydrogen Peroxide in the Redox Regulation of Angiotensin II-Induced Sympathoexcitation Grant: $280,000 from January 2009 to December 2012 Funding agency: American Heart Association Scientist Development Grant Role: Principal investigator

Sympathetic Control in Heart Failure: A Role for Statins Grant: $627,151 from July 2009 to June 2011 Funding agency: NIH Role: Co-investigator Neuro-Circulatory Function in Chronic Heart Failure Grant: $6,166,355 from July 2009 to June 2014 Funding agency: NIH Role: Co-investigator

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Jered Garrison, Ph.D.

DRUGS DESIGNED TO “GO RAMBO” IN PANCREAS CANCER CELLS A stealth Rambo-like drug that sneaks into enemy cancer cells in the pancreas then goes on a rampage while sparing innocent, healthy cells and organs is being developed in the laboratory of Jered Garrison, Ph.D. Dr. Garrison’s copolymer drug delivery system will deposit large amounts of radioactive drugs directly into the tumor, and reduce toxicity to healthy tissues.

“A major drawback of many of the current nanomedicine drug delivery systems is that they are themselves toxic, especially to the liver and spleen,” said Dr. Garrison, a native of Marion, Ohio.

Anywhere from 1 percent to 20 percent of the drug is picked up by the liver, the body’s filtration system, and the spleen. Dr. Garrison’s new polymer uses a protein to break a linking peptide that allows the liver and spleen to clear the drug and reduce toxicity in these normal, healthy tissues.

If it works, it will greatly increase the amount of drug that can be given to a patient and provide better diagnosis and therapy.

In the United States, pancreatic cancer is the fourth leading cause of cancer-related death in both men and women. Pancreatic cancer is diagnosed

by X-ray, MRI or CT scans, followed by an invasive biopsy to confirm.

It is often called the “silent killer” because diagnosis usually occurs at an advanced stage. The survival rate is poor compared with that of other types of cancer. Therapy options are slim and the five-year survival rate is less than 5 percent once diagnosed.

Dr. Garrison’s secret Rambo weapon is a radioactive metal, Lutetium 177, which has been approved in Europe and recently in the United States, for imaging and therapy clinical trials. Even though he works with small amounts, he must wear protective gear and a dose meter to monitor his exposure.

Surinder Batra, Ph.D.

“Pancreatic tumors are more solid and back pressure prevents drugs from getting to the tumor. It’s like the drugs hit a brick wall,” Dr. Garrison said.

The radioactive drug is able to penetrate further, spread wider and cut DNA, causing tumor cells to die.

In addition, because it’s radioactive, the drug’s progress can be followed by medical imaging techniques.

Dr. Garrison arrived at UNMC in October 2009 as a recruit from the University of Missouri-Columbia where he was doing post-doc research. His research began as a seed project and quickly advanced to a full project after the review board determined he had made significant progress.

His mentor is Surinder Batra, Ph.D. “Dr. Batra helps me navigate the UNMC system and gives me advice on mentoring others,” said Dr. Garrison, who now works with one graduate student and two post-docs and has just begun to teach.

“He provides a tremendous amount of expertise and experience to this project from which I can draw. Dr. Batra has been a remarkable mentor.

He offers me a unique perspective that has encouraged my development as a scientist and faculty member at UNMC,” Dr. Garrison said.

The two meet monthly to review Dr. Garrison’s progress.

“Dr. Garrison’s research represents new real thinking about the disease and how to deliver drugs designed for that disease,” Dr. Batra said. “This is a great translational research project.

“Jered is a good scientist and he’s great to mentor. I love helping young faculty develop preliminary data so they can find new funding.”

The 2010 recipient of UNMC’s Outstanding Mentor of Graduate Students Award, Dr. Batra said that to be a successful mentor one must make him or herself available to the mentee.

“A successful mentor is one who listens to his mentees and guides them in the right direction, while still allowing the mentees to have their own individualism.

Most importantly, a mentor inspires by seeing the possibilities and bringing to life the qualities we aspire for ourselves,” he said.

Dr. Batra is one of UNMC’s top researchers. His research is focused on identification, characterization and application of novel genes and gene products for cancers, particularly pancreatic cancer. Since coming to UNMC, he has brought in more than $9.5 million in total research funding.

Dr. Batra also is among UNMC’s most accomplished inventors. Research from his group has led to six U.S. patents and several technologies and reagents, which are being marketed to technology companies. He was named one of UNMC’s Distinguished Scientists in 2006.

In addition to his research, Dr. Batra is involved in teaching medical, pharmacy and graduate students and in developing training programs for graduate and summer students at UNMC. Several graduate students and postdocs in his research group are funded by his various grants.

COBRE Project 5: Development of Cleavable Linkers for Enhanced Diagnostic Imaging and Radiotherapy Principal investigator: Jered Garrison, Ph.D. Assistant Professor of Pharmaceutical Sciences

Mentor: Surinder Batra, Ph.D. Professor and Chairman of Biochemistry and Molecular Biology and Associate Director of Education and Training

Grant: $185,625 for one year Dr.Garrison’s other grants: Design and Evaluation of Hypoxia Enhanced Bombesin Analogs for Prostate Cancer Grant: $983,303 from September 2008 to February 2013 Funding agency: NCI - NIH Pathway to Independence Award (K99/R00) Role: Principal investigator Diagnostic Copper-64 Bombesin Radiopharmaceuticals for Prostate Cancer Grant: $138,000 (Awarded, but terminated early due to concurrent funding) from July 2007 to June 2010 Funding agency: Canary Foundation/

American Cancer Society Postdoctoral Fellowship Role: Principal investigator Development of Therapeutic Copper-64 Radiopharmaceuticals for Prostate Cancer Grant: $149,200 (Awarded, but declined due to concurrent funding) from April 2007 to March 2010 Funding agency: National Research Service Award — NCI Postdoctoral Fellowship Role: Principal investigator

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Matthew Kelso, Pharm.D., Ph.D.

ROLE OF INFLAMMATION IS EXAMINED IN TRAUMATIC BRAIN INJURY RESEARCH Traumatic brain injury (TBI) has become a significant public health concern in the United States because of the on-going conflicts in Iraq and Afghanistan. An estimated one-sixth of the soldiers serving in Iraq have suffered at least one concussion during their deployment — typically during combat or from a blast.

There is no treatment for neuronal damage due to trauma, but a therapy studied by Matthew Kelso, Pharm.D., Ph.D., would protect the brain from permanent damage.

Injury to the brain sets off a biochemical cascade that creates an

imbalance between the production of superoxide radicals and its regulator, superoxide dismutases or SOD. “Production of radicals increases while SOD decreases, leading to the production of even more toxic radicals,” he said.

Superoxides are free radicals produced during normal cellular respiration. Because superoxides are toxic, the body produces SOD scavenging enzymes to keep superoxides in check.

SOD is an important antioxidant defense mechanism.

Dr. Kelso uses a special nanoZYME developed in the Center for Drug Delivery and Nanomedicine to deliver extra SOD

to the site of injury, reduce inflammation and prevent cell death. This special nanoZYME penetrates the blood brain barrier and target sites of inflammation.

Preliminary data shows improvement in the brain in tests with rats. Dr. Kelso plans to submit additional grants to further this study.

A Nebraska native, he received his doctorate in pharmacy from UNMC in 2003. The CoBRE grant was part of the recruitment package that lured him from the University of Kentucky, where he earned his doctorate in pharmaceutical sciences in 2009.

Howard Gendelman, M.D.

“Matt’s studies examine how the brain changes after a traumatic insult. Not only are these studies important for the military, but they have implications for anyone who suffers a head injury,” said Howard Gendelman, M.D., professor and chairman, pharmacology and experimental neuroscience.

Dr. Gendelman’s own research identifies changes that occur during neuroinflammatory responses seen during Parkinson’s and Alzheimer’s disease as well as HIV-associated neurocognitive disorders.

“Dr. Kelso’s research is important to mine in that there may be critical changes in inflammatory responses in the brain seen during traumatic brain injury that could influence nerve cell degeneration, which contribute to the pathogenesis of many disorders of the brain that we study,” he said.

“When Matt approached me to be his mentor, I felt honored to help him carry on with this important area of research. As I help Matt, I also will learn a great deal about traumatic brain injury from him. I hope this starts many years of collaborative research,” Dr. Gendelman said.

Seed Project: Efficacy of Superoxide Dismutase Polymer Conjugates for the Treatment of Oxidative Damage Induced by Traumatic Brain Injury Principal investigator: Matthew Kelso, Pharm.D., Ph.D. Assistant Professor, Pharmacy Practice

Mentor: Howard Gendelman, M.D. Professor and Chairman, Dept. of Pharmacology and Experimental Neuroscience

Grant: $50,000 for one year Dr. Kelso’s other grants: Magnetic resonance elastography of a traumatic brain injury mouse model Grant: $100,000 from July 2010 to June 2012 Funding agency: University of Nebraska-Lincoln Role: Principal investigator Biotek Epoch Multi-Volume Spectrophotometer System Grant: $11,415 from July 2010 to July 2011 Funding agency: Nebraska Bankers Association Role: Principal investigator

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bioimaging

Michael Boska, Ph.D.

CORE LABORATORIES Michael Boska, Ph.D., professor and vice chairman for research, radiology, directs the Bioimaging Core. He helps new investigators design the best medical and molecular imaging experiment and analysis for their small animal models.

The Bioimaging Core provides researchers the ability to see and measure: • Nanomaterial biodistribution — the amount of drug at the targeted designation; • Pharmacokinetics — how much was delivered to regions of the body and how long it remains in the tissue, and; • Therapeutic efficacy — the drug’s effectiveness and side effects.

“Researchers can actually see in

3D where their pre-clinical drug loaded nanomaterial is going and whether the formulation is halting or reversing the progress of the disease,” Dr. Boska said.

“It’s as if we’re in outer space looking at the lights of metropolitan cities at night,” he said. “Disease targets illuminate with the help of radiolabeled or magnetically labeled drug-loaded nanomaterials. We can see how much of the nanomaterial has been delivered and how long it stays there.”

The lab has performed scans of mice and rats to detect neurodegeneration due to traumatic brain injury, HIV infection, Parkinson’s disease and Alzheimer’s disease. In addition, studies have been performed to detect viral inflammation of the spinal cord, measure efficacy and

response kinetics of nanoparticle-based therapy on drug resistant tumors in mice and measure the biodistribution of nanoparticle-based contrast agents for detection of rheumatoid arthritis.

“Dr. Sasha Kabanov has assembled a critical mass of investigators who have come together to find solutions,” Dr. Boska said. “A synergy has developed among these scientists.

“We have a special kind of interdepartmental collaboration in Nebraska. This is an ideal environment for people to work together from different departments and scientific disciplines and conduct the best science. In other places, barriers to cross departmental lines and share grant applications make this type of collaboration difficult at best.”

nanomaterials

Tatiana Bronich, Ph.D

PROVIDE CRITICAL SUPPORT Tatiana Bronich, Ph.D., associate director of the Center for Drug Delivery and Nanomedicine and professor of pharmaceutical sciences, directs the Nanomaterials Core.

The Nanomaterials Core supports COBRE project leaders in the development of nanoscale polymer materials for drug delivery, their characterization and safety evaluation.

Dr. Bronich and her team use stateof-the-art equipment to produce materials for biomedical research and develop new technologies not yet employed in research. Core researchers are developing nanozymes as a platform technology for delivery of antioxidant proteins, polymeric carriers for the delivery

of antiviral peptides as well as novel polymer conjugates.

In the growing field of personalized medicine, nanomaterials have a unique niche. “One system can simultaneously diagnose, treat and then follow the treatment using reporter molecules that show what’s going on in a noninvasive way,” she said.

“Innovation is the exciting part of this job,” Dr. Bronich said. “We’re working with new materials that are responsive to external stimuli — for example, magnetic field or optical signal — so we can purposely switch the drug system on and off. We can deliver a drug to a site in the body and have it wait there until we send a signal from outside.” The external signal is like a key in an ignition — it

won’t activate an engine (drug) until the key is turned.

“This could be an enormously useful tool for clinicians,” she said. “Once the drug is docked at the cell, then we can tell it when and how much to deliver. In many diseases, it’s critical that the drug actively deliver to its target over a long period of time.

“Our goal for the Nanomaterials Core is to provide researchers a toolbox of resources that can be used by the entire UNMC community,” she said.

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Nanomedicine research grows at UNMC Nebraska’s soil is home to an array of crops, but it’s also fertile ground for growing science - some of which is 100,000 times smaller than the head of a pin.

Alexander “Sasha” Kabanov, Ph.D., D.Sc., has cultivated that growth since 1994, when he arrived at UNMC without funding, but rich in dreams.

Within five months he was awarded his first grant and by 2004, he realized his first major vision — the Center for Drug Delivery and Nanomedicine (CDDN). One of the first such centers in the world, the CDDN has grown to support 33 faculty members who hold more than $34 million in federal research funding.

The center has catapulted the UNMC College of Pharmacy in 2009 into fourth place in the National Institutes of Health (NIH) ranking of funding for pharmacy faculty in the United States.

Nanomedicine develops materials and devices at the nanoscale level to diagnose, treat and monitor diseases.

Nanomedicine could yield implantable devices, 100,000 times smaller than the head of a pin, that will effectively detect diseases without surgical invasion and eradicate the diseased cells by precisely “pumping” medicine into them.

Dr. Kabanov’s research has impacted the field of nanomedicine in profound ways. He developed such novel nanomedicine principles as polyelectrolyte complexes for gene and drug delivery, his pioneering work led to clinical trials using polymer micelles, and he coined the term ‘polymer genomics’— how polymers influence genetic makeup and express profiles in genes.

While building the center, the Parke-Davis Professor in Pharmaceutics and director of the CDDN had the foresight to seek support beyond merit-based funding and build interdisciplinary collaborations as well — across campus, across the country and around the world.

Congressional earmarks Earmarks are line-items in Congressional spending bills that allocate funding for a specific program or project.

The CDDN has received earmarks with the help of U.S. Sen. Ben Nelson of Nebraska and other members of Congress, who support projects for the health of the nation and its economy. Nelson has helped secure more than $55 million in earmark funds for UNMC during the past six years for such projects as non-invasive nanodiagnostics of cancer, and two collaborative projects with Iowa State University: synthetic nanovaccines against respiratory pathogens and targeted nanovaccine platforms against respiratory pathogens.

The earmark process is an appropriate use of such money. Sen. Nelson said he will continue to pursue funding in a transparent manner to support worthy projects that keep Nebraska competitive nationally.

Non-invasive nanodiagnostics of cancer A special early detection system for cancer has been developed by a group led by Alexander “Sasha” Kabanov, Ph.D., D.Sc., that seeks out cancerous cells, lights them up and makes them visible for various imaging techniques.

The four-year, $1.8 million grant from the U.S. Army was awarded in 2007 to develop noninvasive diagnostics that detect cancer in its earliest, most easily treatable, presymptomatic stage. This system finds cancer that conventional diagnostic methods would never find.

“The polymers are multifunctional,” said Tatiana Bronich, Ph.D., associate director of the CDDN and professor of pharmaceutical sciences. “We can use them to attach to the cancer cell or imbed in them to track over a long period of time.” Dr. Bronich is the first woman to be appointed a professor position in UNMC’s College of Pharmacy.

Lee Mosley, Ph.D., associate professor of pharmacology and experimental neuroscience, and Michael Boska, Ph.D., professor and vice chairman for research, radiology, collaborated on this project.

The nanocarriers can be loaded with different imaging and diagnostic molecules that allow for multiple methods of detection — from single photon emission computed tomography (SPECT) to positron emission tomography (PET) and magnetic resonance imaging (MRI). “Every imaging technology has its own sensitivity and resolution,” Dr. Bronich said.

The project resulted in an international collaboration and an agreement for scientific and educational exchange and cooperation between UNMC and University Tsukuba in Japan. A visiting assistant professor from Tsukuba worked with UNMC researchers on the project, which resulted in a joint publication.

“Next, we’re going to apply this technology to pancreatic cancer,” Dr. Bronich said.

Collaboration already has begun with Surinder Batra, Ph.D., professor and chairman of the department of biochemistry and molecular biology, whose research is focused on pancreatic cancer.

Targeted nanovaccine platforms against respiratory pathogens The collaboration between UNMC and Iowa State University (ISU) to develop novel vaccines for central nervous system disorders was expanded with an earmark secured by U.S. Sen. Tom Harkin for $2 million. UNMC has received $850,000 from this grant.

Researchers will use polymeric nanomaterials developed by UNMC and ISU that have successfully delivered proteins/polypeptides to treat cancer,

neurodegenerative disorders and infectious diseases.

These delivery systems also demonstrated the ability to alter or regulate one or more immune functions by targeting specific cells to spark immune responses. They will be used to develop nanovaccines to fight respiratory pathogens, specifically, influenza virus A. There are three major strains of influenza virus A circulating in human populations — influenza A H3N2 and

H1N1, both associated with seasonal flu epidemics, and the new swine-origin H1N1 pandemic strain. In addition, an avian influenza virus, A H5N1, is capable of causing disease in domestic and wild birds.

“These investments will help fortify America’s defenses while boosting the state’s economy,” Sen. Harkin said.

“This initiative will bolster our national security and protect our men and women in uniform.”

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SYNTHETIC NANOVACCINES PROTECT AGAINST RESPIRATORY PATHOGENS

To protect soldiers against airborne bacterial pathogens and chemical weapons engineered to attack the central nervous system, UNMC is collaborating with Iowa State University (ISU) to develop single dose vaccines that boost the immune system.

The five-year, $3.4 million grant from the U.S. Army also has been an exercise in Congressional collaboration as Sen. Ben Nelson worked with Iowa Sens. Chuck Grassley and Tom Harkin to secure continued funding for the project that began in 2008. The funds are equally divided between two institutions.

“This valuable collaboration taps expertise on both campuses,” said Mark Bowen, director of government relations at UNMC. “It has military and civilian applications — it benefits everyone. Chemicals used in agriculture are the same as those used in warfare for biological weapons, just mixed differently.”

The researchers evaluate three novel nanotechnology platforms based on safe and degradable adjuvant polymer systems that enhance antigen presentation and stimulate immunity.

The first target: H5N1, or avian flu, a significant pandemic threat when it quickly spread around the world, reaching a peak in 2006. H5N1 is highly contagious and mutates quickly. Last year, 17 countries throughout Europe, Asia, Africa and the Middle East reported outbreaks of H5N1 in domestic poultry and wild birds.

So far, the spread of H5N1 virus from person-to-person has been rare, limited and unsustained. The World Health Organization reports that overall mortality in reported H5N1 cases is approximately 60 percent. The majority of cases have

occurred among children and adults under 40.

Humans have little pre-existing natural immunity to the H5N1 virus infection. If H5N1 viruses gain the ability for efficient and sustained transmission among humans, an influenza pandemic could result with potentially high rates of illness and death worldwide.

To attack this problem, Dr. Alexander “Sasha” Kabanov, Ph.D., D.Sc., has recruited researchers from the fields of microbiology, biochemistry, virology, immunology, materials science and engineering.

ISU experts in biomaterials for drugs, vaccines and gene delivery, tissue engineering and veterinary microbiology collaborate with UNMC experts in polymer chemistry, biosecurity, microbiology and aerosol vaccination techniques.

Dr. Kabanov hopes to adopt platforms to develop vaccines for other respiratory infections such as pulmonary tularemia, which the U.S. government classifies as a Class A agent, meaning it has the potential to pose a severe threat to public health and safety.

Last year, the project was expanded to develop a vaccine against such disorders of the central nervous system (CNS) as Parkinson’s disease, which can develop naturally through either environmental or genetic factors or through exposure to chemical weapons.

This portion of the project is led by Howard Gendelman, M.D., the Larson Professor of Internal Medicine and Infectious Diseases, chairman of the department of pharmacology and experimental neuroscience and director of the Center for Neurovirology and

Neurodegenerative Disorders (CNND) at UNMC. He will evaluate the three nanotechnology platforms to determine which improves protection, defends the brain against the disease and reduces toxicity to the body. Dr. Gendelman said human studies are being conducted at the University of Alabama-Birmingham and at UNMC to see if immune deficits seen in mice also are present in humans with Parkinson’s disease.

The cause of Parkinson’s disease — which affects more than 4 million people worldwide — is the loss of neurons that produce dopamine, a nerve signaling chemical that controls movement and balance.

Neurodegeneration occurs when a normal protein called alpha synuclein clumps, changes shape, then accumulates in the brain. This results in the body attacking it through inflammation and causing destruction of dopamineproducing nerve cells.

UNMC researchers reversed the neurodegenerative effects of alpha synuclein by changing immune responses to it.

In mice with an experimental form of Parkinson’s disease, researchers found that the vaccine enabled T cells to migrate to the damaged area of the brain and trigger a neuroprotective response that reduced disease-linked reactions in the brain. T cells are white blood cells that are key to the immune response. They act like soldiers who search out and destroy targeted invaders.

17

NIH GRANTS Researchers in the CDDN have been aggressive in pursuing grants from the National Institutes of Health (NIH), National Science Foundation and other organizations.

Here are highlights of the major grants from the NIH.

Robert Luxenhofer, Ph.D.,

UNMC’s nanomedicine team recently joined elite scientific club in the United States to develop more effective treatments for cancer. Alexander “Sasha” Kabanov, Ph.D., D.Sc., director of the Center for Drug Delivery and Nanomedicine, received a five-year, $2.2 million grant from the National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer program.

UNMC is now part of the prestigious Nanotechnology Platform Partnership, one of four programs launched by the NCI Alliance.

With this grant, UNMC researchers will address the critical need for early diagnosis of, and more effective treatments for, HER2 breast cancer, which is characterized by aggressive growth and poor prognosis. Breast cancer was responsible for 40,000 deaths in the United States last year.

“About one-third of the patients who have this type of breast cancer do not respond to current therapies and, eventually, all become drug resistant,” Dr. Kabanov said.

“We have developed a novel polymer micelle system for the delivery of paclitaxel, a potent chemotherapy agent, which is highly insoluble,” he said. “It acts like it’s on a search and destroy mission — it delivers the drug straight to the cancer cell, but the polymer used is 100 times less toxic than current commercial drug formulations.”

The grant is the largest interdisciplinary collaboration between researchers in the CDDN, the UNMC Eppley Cancer Center and Dresden Technical University in Germany.

Representing the CDDN is Dr. Kabanov and Tatiana Bronich, Ph.D., associate director of the CDDN and professor of pharmaceutical sciences.

Dr. Bronich directs the Nanomaterials Core laboratory where nanoparticles are designed to deliver drugs to specific targets.

They work with breast cancer biology experts Hamid Band, M.D., Ph.D., professor and director of the Center for Breast Cancer Research and associate director of education and training for the Eppley Cancer Center, and Srikumar Raja, Ph.D., research assistant professor, Eppley Institute.

“I’m alarmed that breast cancer is increasing among younger women,” Dr. Band said.

Hamid Band, M.D., Ph.D.

High Capacity Nanocarriers for Cancer Chemotherapeutics “Many women will develop cancer in their 30s and 40s. It’s important that we create something that will work for them.”

The American Cancer Society reports that breast cancer is now the leading cause of cancer death in young women ages 15 to 54. In the United States, cancer accounts for one in every four deaths.

“Our goal is to be close to clinical translation by the end of our five-year grant,” Dr. Band said.

Collaborating from Germany are Rainer Jordan, Ph.D., professor of macromolecular chemistry, and Robert Luxenhofer, Ph.D., a research fellow in chemistry, who was a post-doc in Dr. Kabanov’s lab for nearly two years.

“The new nanoformulation of paclitaxel can transport a large amount of chemotherapy drugs directly to the cancer resistant cells and greatly reduce side

effects,” Dr. Luxenhofer said. “Patients would receive shorter infusions and experience less toxic effects.”

The technology was invented by Drs. Jordan, Luxenhofer and Kabanov and co-patented by UNeMed, UNMC’s technology transfer arm, and Bayerische Patentallianz, the technology transfer arm for the Technical Universities of Munich and Dresden.

The NCI grant is part of the second phase of the Alliance for Nanotechnology in Cancer program, through which about $30 million per year will be invested in multi-institution grants for the next five years.

The Nanotechnology Platform Partnerships are dedicated to the advancement of nanotechnology discoveries and their transformation into cancer-relevant applications with clinical utility. Researchers involved in

the program have developed a host of novel technologies, with several of them undergoing commercialization and clinical trials.

Other institutions that are part of the partnerships are Cedars-Sinai Medical Center, Los Angeles; Children’s Hospital of Los Angeles; Emory University, Atlanta; Northeastern University, Boston; Northwestern University in Evanston, Ill.; Rice University, Houston; University of Cincinnati in Ohio; University of North Carolina School of Medicine, Chapel Hill; University of New Mexico Health Sciences Center, Albuquerque; and the University of Utah, Salt Lake City.

19

Polypeptide Modification Enhances Brain Delivery Another collaborative project — with University of Washington, St. Louis University School of Medicine and Virginia Polytechnic Institute and State University, Blacksburg — seeks to find an effective therapy for obesity.

The four-year, $1.9 million grant from the National Institute of Neurological Disorders and Stroke is a renewal of a grant that was first awarded in 2006.

“The long-term goal is to develop therapeutics for diseases or medical problems related to the central nervous system,” said Alexander “Sasha” Kabanov, Ph.D., D.Sc., director of the Center for Drug Delivery and Nanomedicine. “Our preliminary results with obesity have been extraordinarily successful.”

The team is modifying a polypeptide — leptin — with Pluronic block copolymers so it can cross the blood-brain barrier. Leptin is a hormone that regulates appetite and eating behavior. It is naturally produced when eating and alerts the brain that the stomach is full. In some obese people, however, the leptin transporters in the brain do not work.

“We hope to use plurionic block copolymers to transport leptin to the brain to help those people whose transporters are not functioning,” Dr. Kabanov said.

Collaborators are: William Banks, M.D., professor of gerontology and geriatric medicine at University of Washington, Susan Farr, Ph.D., associate professor of geriatrics at St. Louis University School of Medicine; and Judy Riffle, Ph.D., professor of chemistry, and director of macromolecular science and engineering education at Virginia Tech. Dr. Riffle will generate new block copolymer analogs for polypeptide modification. She and Dr. Kabanov each have supervised students and student exchange visits between UNMC and Virginia Tech.

An expert in transport of polypeptides to the central nervous system, Dr. Banks will administer the research on protein modification and receptor binding and transport of modified polypeptides in vitro. He developed all the obese mouse models used for these studies.

Polymer Based Gene Delivery A vaccine for melanoma is the goal of this collaborative project between UNMC and the Memorial Sloan Kettering Cancer Center in New York City. The five-year, $1.3 million project was funded by the National Cancer Institute in 2006.

UNMC researchers will use nonionic block copolymers that have successfully transferred genetic material to muscles and have been shown to be safe in human clinical trials for cancer chemotherapy. The goal is to evaluate this system for delivery of DNA vaccines targeting malignant melanoma in mouse models.

Sloan Kettering researchers have expertise in pre-clinical and clinical DNA immunizations against malignant melanoma.

Interactions of Pluronic Block Copolymers in Drug Resistant Cancer Cancer is a leading cause of death worldwide, accounting for 7.9 million deaths in 2007. In the United States, cancer is the second most common cause of death, exceeded only by heart disease.

This year, 569,490 Americans are expected to die from cancer, more than 1,500 people a day, according to the American Cancer Society.

Also, more than 1.5 million new cases of cancer are expected to be diagnosed in the United States this year.

Multidrug resistance (MDR) has become a major obstacle to effective chemotherapy treatment.

MDR is the phenomenon in which exposure of tumor cells to a single cytotoxic agent accounts for crossresistance to other structurally unrelated classes of cytotoxic agents.

Researchers in the Center for Drug Delivery and Nanomedicine hope to improve treatment by using a drug delivery system that sensitizes the cancer tumor to chemotherapeutic drugs. This five-year, $1.2 million grant from the National Cancer Institute was renewed in 2007. Researchers at Virginia Polytechnic Institute and State University, Blacksburg, also are collaborating on the project, which will use fluorescence resonance energy transfer to track the amount of drug that makes it into the tumor.

The polymer-based drug SP1049C co-developed

by Kabanov in collaboration with Supratek Pharma Inc. (Montreal, Canada) have shown high promise in treatment of highly resistant esophageal cancer in Phase II clinical trials.

21

Howard Gendelman, M.D., with his research team

NEW AIDS TREATMENT ON THE HORIZON Two brilliant researchers at UNMC have joined forces to tackle stroke, neuro-AIDS and Parkinson’s disease — some of the most vexing medical problems facing the human race today.

The transformative partnership between Howard Gendelman, M.D., and Alexander “Sasha” Kabanov, Ph.D., D.Sc., has taken science to a new level.

Their latest collaboration — to develop a nanoformulated antiretroviral therapy (ART) — could revolutionize the treatment of HIV and AIDS by delivering a month’s worth of therapy in a single pill.

The project is funded by a threeyear, $4.6 million program project grant from the National Institutes of Health, National Institute on Drug Abuse. The grant was awarded to Dr. Gendelman, the Larson Professor of Internal Medicine and Infectious Diseases, chairman of pharmacology and experimental neuroscience and director of the Center

for Neurovirology and Neurodegenerative Disorders at UNMC. The grant — titled “NanoART — Manufacture, Delivery and Pharmacokinetics for Optimizing Drug Adherence,” — brings together 14 investigators from UNMC and New York’s Columbia University Medical Center and St. Luke’s-Roosevelt Hospital Center.

Dr. Kabanov, the Parke-Davis Professor in Pharmaceutics and director of the Center for Drug Delivery and Nanomedicine (CDDN), is one of three principal investigators. Together with Tatiana Bronich, Ph.D., associate director of the CDDN and professor of pharmaceutical sciences, they will design and create the nanoformulations for this project.

Other teams will study how the drug acts in the body and will perform tests on animal models with the hopes of reaching human clinical trials, Dr. Gendelman said.

“Success will lay the foundation for subsequent bench-to-bedside research toward pioneering long-acting injectable ART for noncompliant patients,” he said.

NanoART will address the following problems with current HIV/AIDS therapy, Dr. Gendelman said: • HIV therapy is lifelong and complex. There are many pills that need to be taken each day and for the rest of a patient’s life.

• While therapies prolong life, they also increase toxicity because of the length of treatment.

• Medications do not destroy the viral reservoirs in the body.

• Patients who have HIV/AIDS — drug addicts, IV users and people in remote areas of Africa — experience the most difficulty with medication compliance.

“If they only have one pill a month to take, that’s a big advance in HIV/AIDS therapy,” Dr. Gendelman said.

Friendship Cultivates Start-up Company A 15-year friendship blossomed into a research collaboration that has turned two UNMC scientists into business partners.

“It’s a rare opportunity to meet someone who changes your life in such a way that it leads to new ideas.

It transforms the way you think and the way you shape your career,” said Howard Gendelman, M.D. “Sasha and I share a journey. There have been thorns along the way, but the science we’ve done together will most likely be successful,” he said.

Dr. Gendelman defined the field of neuroimmunology pharmacology, wrote a textbook on the subject and five years ago started the Journal of Neuroimmune Pharmacology, which has become the second leading journal in the field. He

believes he has found an effective way to treat many brain-related diseases.

Dr. Kabanov has made a profound impact on the field of nanomedicine by establishing some of its basic principles.

He knows how to build vehicles that can safely deliver those drugs directly to the point of disease.

The two men began collaborating several years ago on a vaccine for Parkinson’s disease and new treatments for HIV/AIDS. Since then, the two have formed a company, Neuropel Pharma Inc., to develop therapeutics for these diseases, and have plans to expand their business collaborations.

23

Alexander V. Kabanov, Ph.D., and Anna Brynskih, M.S.

TRANSLATING RESEARCH IS NOT EASY Researchers at UNMC work diligently to discover cures for Parkinson’s disease, stroke, brain trauma and other neurological conditions.

Such cures could be found using a new drug called NanoZYME, trademarked

by Alexander “Sasha” Kabanov, Ph.D., D.Sc., professor of pharmaceutics and director of the Center for Drug Delivery and Nanomedicine (CDDN).

The drug is a critical component within the CDDN’s goals of building an institute for translational nanomedicine.

“The NanoZYME is an enzyme packed into polymer particles, or containers.

This technology allows the delivery of the therapeutic enzymes to the disease or injured site,” said graduate student Anna Brynshikh. “These enzymes are antioxidants that attack destructive free radicals in the brain, which are common in Parkinson’s disease, traumatic brain injury, stroke and many other neurological conditions.”

For stroke patients, every minute counts. A six-hour window of opportunity exists from the initial attack to the administration of thrombolytic drugs to limit stroke damage and disability.

Medication given after that time could

cause a brain hemorrhage.

“A patient with acute ischemic stroke symptoms could be safely treated with the NanoZYME therapy at any time without waiting for diagnostic tests,” said Brynshikh, who works on the stroke project. “It could be administered on site by the EMT and it won’t hurt the patient if it’s later determined that there was no stroke.”

Although stroke is one of many neurological disorders that could benefit from such therapy, Dr. Kabanov says a translational research approach is pervasive in all CDDN projects.

That approach is key to his philosophy and vision for the institute.

“This will be a place where researchers publish in the best journals, star students compete for graduate positions and patient treatments are developed.

“We’re on track for this,” he said. “It could develop into a translational patient treatment center that will bring economic advantages and global recognition to the state.”

Every project in the CDDN begins with a therapeutic or diagnostic goal.

Every project has a team of basic researchers and clinical physicians who

regularly meet to improve projects and study designs. The approach is referred to by Dr. Kabanov as Conceptual Reversed Product Engineering (CRPE), a new model in translational research design and implementation.

In CRPE, team members discuss practical goals of their research and ask marketing-type questions not normally heard in the halls of academic science — whom will be treated, what are the treatment regiments and routes of administration, what is the competition and how big is the target market, said Brynshikh, who also coordinates the CRPE series.

And every project has a plan on how to cross the dreaded valley of death (see article on page 26).

Dr. Kabanov and his team boast more than $34 million in federal research grants and generate about 50 percent of all UNMC patent applications. Still, he wants to see new therapies evolve from their work.

“We spend huge amounts of money on research, but don’t do a very good job of translating it into practical medicine,” he said. “There should be a better return on the taxpayer’s investment.”

Elena Batrakova knows the rewards of translational research Shortly after coming to Omaha 15 years ago, Elena Batrakova, Ph.D., attended a conference where she heard Purdue University’s Philip Low, Ph.D., talk about a folate receptor he first used for targeted delivery and diagnostics.

Folate receptors are found on many cancer cells.

“At the conference two years ago,” Dr. Batrakova said, “he brought a surgeon from Norway who talked about how he used Dr. Low’s invention to tag cancer cells with a fluorescent dye that lights up and shows where cancer cells are hiding.

“It’s the dream of every scientist to see their formulation help people,” she said. “If at least one person is helped, that’s more rewarding than publishing 100 papers in Science. It’s always the goal — bench to bedside — but it takes a long time. A treatment that works is not easy to reach and requires decades of research. Without basic research, we’ll never get good treatments for people.”

Dr. Batrakova, research associate professor of pharmaceutical science, was one of three polymer scientists who followed Alexander “Sasha” Kabanov, Ph.D., D.Sc., professor of pharmaceutics and director of the Center for Drug Delivery and Nanomedicine, from Moscow to Omaha in 1996.

She works on her own drug formulation, which may one day help people with Parkinson’s disease.

25

BRIDGING THE VALLEY OF DEATH There is growing frustration among the research community with how few discoveries translate from the basic science lab to the patient’s bedside.

Consider: • It takes 15 to 20 years, on average, to develop new therapies and drugs.

• Between 1996 and 1990, the U.S. Food and Drug Administration (FDA) approved 157 new drugs.

Michael Dixon, Ph.D.

In the same time period a decade later — from 2006 to 2009 — the agency approved 74. None were cures or effective treatments for some of the biggest medical issues facing people today.

• The cost of getting a drug to market, from pre-clinical research, through regulation and then to marketing, is $1.2 billion.

• Nine out of 10 drugs fail to get to the marketplace.

Many biomedical discoveries never advance beyond publication in a scientific journal due to a lack of resources or insurmountable red tape. The issue is so prevalent that researchers have coined the term “the valley of death” to describe why promising discoveries, such as genes linked to cancer and Parkinson’s disease, languish in the laboratory.

In April 2008, former U.S. Sen. Arlen Specter of Pennsylvania added a piece to the health care reform bill that created CAN — Cures Acceleration Network — an independent agency dedicated to advancing science from the laboratory into practice. Sen. Specter, a two-time cancer survivor, challenged researchers to “cure something.”

CAN will be established within the Office of the Director of the National Institutes of Health (NIH) to conduct and support “revolutionary advances” in translating scientific discoveries from bench to bedside. The proposed 2012 budget for CAN is $100,000 million.

The NIH also has other resources — established and just developing — to help scientists with translational research.

One such resource is the Alliance for Nanotechnology in Cancer program through the National Cancer Institute (NCI). Alexander “Sasha” Kabanov, Ph.D., D.Sc., professor of pharmaceutics and director of the Center for Drug Delivery and Nanomedicine, received a five-year, $2.2 million grant to become part of the

prestigious Nanotechnology Platform Partnership, one of four programs launched by the NCI Alliance.

With this grant, UNMC’s nanomedicine team joined the most elite scientific club in the United States to develop more effective treatments for cancer. To help researchers get one step closer to translating their discoveries to the marketplace, the Alliance offers assistance through the Nanotechnology Characterization Lab (NCL), said Rachael Crist, Ph.D., data coordinator and scientific writer with the NCL. “We serve as a free, national resource and knowledge base for all cancer researchers and provide preclinical characterization for researchers before they file an investigational new drug application with the Food and Drug Administration. As with any independent third-party validation, inclusion of NCL data may make an application stronger,” she said.

Dr. Kabanov wants to develop funding sources to help UNMC’s translational researchers cross the

ACADEMIA

valley of death, said Michael Dixon, Ph.D., director of UNeMED Corporation, UNMC’s technology commercialization arm.

“Sasha is positioned to build a biotechnology business in Omaha. He’s working to generate data to structure a new company that will draw on resources developed in his center,” he said.

Dr. Kabanov’s group has become the most prolific inventors on campus, Dr. Dixon said. “Sasha goes the extra mile to see the invention develop into a clinical therapy that impacts the population.

Because they are creative and innovative, industry knows we’re here.”

To be successful, UNMC must engage in technology development, Dr. Kabanov said. “We must figure out how to bring technologies developed here to the market.

“Our goal is to help the world from Nebraska.”

ACADEMIC RESEARCH, NIH $$

PATENTS

VALLEY OF DEATH

Phase 1

Phase 2

Phase 3 PROOF-OFCONCEPT

Phase 3

PROTYPE TESTING

Phase 1

PROTOTYPE DEVELOPEMNT

Phase 0 INNOVATIVE IDEA

INDUSTRY

disease model A

missing disease model B

missing

disease model C

missing

If you think of a generation of new technology in academia as one mountain peak and the successful commercialization of that technology by industry as another peak, then the space representing the period of time between those two peaks can be seen as a valley.

27

In a field that’s constantly changing, education is the constant Important to any scientific field is the cultivation of new minds that will one day expand that very field of research.

That’s why Alexander “Sasha” Kabanov, Ph.D., D.Sc., provides educational opportunities for researchers interested in learning more about nanomedicine, one of the newest and most promising fields for translational research.

Nanomedicine — a blend of medicine and technology — is multidisciplinary by nature and requires bright minds from many different fields of science.

Scientists work together to build the next generation of nanosized therapies that will: • Deliver drugs and recombinant DNA directly to the disease site to improve medication effectiveness; • Diminish harmful side effects; and • Improve early diagnosis through bioimaging techniques.

Dr. Kabanov, the Parke-Davis Professor in pharmaceutics and director of the Center for Drug Delivery and Nanomedicine, and his team have developed a threetiered program — certificate and seminar programs and an international conference — to address educational needs.

Certificate program launched in the fall of 2010 Last fall, graduate students in physiology at UNMC and engineering at the University of Nebraska-Lincoln inaugurated the first-ever certificate program in nanomedicine for diagnosis and therapy in the United States.

The program provides intensive training and a certificate at the end of the course, which could take one to three years. It is open to graduate students and post-docs in the University of Nebraska system and from other academic institutions and industrial partners in the United States and abroad.

Already, the Center for Drug Delivery and Nanomedicine (CDDN) has research partnerships and student and faculty exchange programs with Iowa State University in Ames, Virginia Polytechnic Institute and State University in Blacksburg, Moscow State University in Russia, Russian State Medical University, University of Tsukuba in Japan and other scientific and educational centers.

The program requires students to complete 12 credit hours, which include two didactic courses, and earn a minimum of a 3.0 grade point average. Research, seminars and presentations can be included in the credit hours. A three-month research project also is part of the program.

A variety of six-credit-hour classes are offered for students who are not normally exposed to such areas as human neuroanatomy, polymer therapeutics, bacterial pathogenesis and medical microbiology. Online courses also are under development.

The program, approved last year by the University of Nebraska Board of Regents, is a collaborative venture between UNMC’s Pharmaceutical Sciences Graduate Program and the CDDN. A member of the program committee, Tatiana Bronich, Ph.D., associate director of the CDDN and professor of pharmaceutical sciences, said it’s important to bridge specialties between the different biomedical fields and nanomedicine.

“We are grooming a new generation of basic, translational and clinical scientists who are capable of conducting state-of-the-art biomedical research that will considerably improve human health around the world,” she said.

“This certificate provides proof of a student’s exposure to nanomedicine and more opportunities beyond academia,” Dr. Bronich said.

UNMC is building nanomedicine brand One of the world’s most prominent chemists is Joseph DeSimone, Ph.D., from the University of North Carolina at Chapel Hill. He presented at the 2010 NanoDDS conference on his particle replication process that promises to revolutionize nano-fabrication techniques.

This is what he said about UNMC students: “Nebraska is making a name for itself in nanomedicine.

“UNMC students are distinguishing themselves at international conferences by asking some of the toughest, most penetrating and challenging questions. At the Gordon Research Conference in August, I was impressed by the depth of the questions coming from Nebraska students. By the end of the meeting, all questioners, students and faculty alike, were prefacing their questions by saying, ‘I’m not from Nebraska, but…’

“It shows the students are well trained. Dr. Kabanov has put together a highly-respected program here,” he said.

“UNMC students are great ambassadors for Nebraska.”

CDDN seminar program

Six times a year, international experts in nanomedicine come to UNMC to lecture on the basic and clinical research they conduct and discuss the challenges of translational research.

The seminar program was initiated in 2005 to bring together diverse technical and scientific expertise in biomedical and material science research and engineering at the University of Nebraska.

Since the beginning of this year, experts have lectured on chemical engineering, neuro-oncology, pharmaceutical sciences, pharmacology and medicine and cellular stress biology. They have come from the University of Michigan, Ann Arbor; Duke University Medical Center, Durham, N.C.; University of Pennsylvania, Philadelphia; Roswell Park Cancer Institute, Buffalo, N.Y.; Northeastern University in Boston; and UNMC. Dr. Kabnov said this is yet another avenue for education in nanomedicine.

“Our seminar programs provide a golden opportunity for young people to meet and hear about the challenges and the innovations in nanomedicine from prominent people working in this field,” he said.

29

nanoDDS CONFERENCES A peer review on steroids.

That’s how the annual three-day International Nanomedicine and Drug Delivery Symposium was described by Joseph DeSimone, Ph.D., professor of chemistry at the University of North Carolina at Chapel Hill and chemical engineering at North Carolina State University, Raleigh.

Nanomedicine’s superstars gather every year at the conference, started by Dr. Alexander “Sasha” Kabanov, Ph.D., D.Sc., director of UNMC’s Center for Drug Delivery and Nanomedicine, to talk about their new discoveries and developments in basic and clinical research. The science that’s presented is so cutting-edge, it’s unpublished.

Following each presentation is a question and answer session, where investigators are grilled by students and colleagues — as in a peer review process.

The 2010 conference, held in Omaha for the third time, marked the eighth year since it began as a humble one-day mini-symposium featuring scientists from UNMC and Japan. Since then, the conference has been held in cities around the United States and Canada. The 2011 conference will be at the University of Utah, Salt Lake City.

“This conference is grounded in history and raises the bar for everyone,” Dr. DeSimone said. “The advantage is that everyone who attends is informed on this topic, unlike at other meetings where there is a wide array of topics being addressed.”

That singular focus and the opportunity for students to mix freely with some of the world’s most prominent experts in nanomedicine is what sets Nano DDS apart from other conferences.

“Nebraska is turning out to be the center of the universe in nanomedicine,” Dr. DeSimone said. “You don’t have a ZIP code advantage either. Traditional centers of medical research are located in Boston, San Diego or the Silicon Valley. Sasha is putting Nebraska on the map and it’s here in the middle of the country — how fitting,” he said.

Dr. DeSimone, a prolific inventor and entrepreneur, has received 40 major awards and recognitions including the 2009 NIH Director’s Pioneer Award and the $500,000 Lemelson-MIT Prize for Invention and Innovation.

His group applies techniques used by the microelectronics industry to the nanomedicine field for the fabrication and

delivery of vaccines and therapeutics. (See article page 29) Students from all over the country and around the world attended the conference.

Four students were in attendance from Virginia Polytechnic Institute and State University, Blacksburg, some of whom have worked in Dr. Kabanov’s laboratory.

Judy Riffle, Ph.D., professor of organic polymer chemistry, and director of Macromolecular Science and Engineering Graduate Studies at Virginia Tech, said the Nano DDS conference is one of the best in the world.

“The group here is unique. It bridges the gap between medicine and basic science. If you are going to make a real difference, you can’t expect one group to do it all in the same institution,” she said.

“The networking done here is invaluable.”

Joseph DeSimone, Ph.D.,

Judy Riffle, Ph.D.,

Professor of Chemistry at the University of North Carolina at Chapel Hill

Professor, Organic Polymer Chemistry Virginia Polytechnic Institute and State University

Christine Allen, Ph.D. Associate Professor, Faculty of Pharmacy at the University of Toronto

NanoDDS embodies the interdisciplinary spirit Christine Allen, Ph.D., associate professor of pharmacy at the University of Toronto, Canada, said she gained a true appreciation for Dr. Alexander “Sasha” Kabanov’s inclusive spirit behind the NanoDDS conference when she helped organize the 2008 conference in Toronto.

“Dr. Kabanov involves women, trainees and junior scientists in this conference,” she said. “Nowhere else can new scientists get up and give short presentations on their work to the world’s experts in this field.

“Sasha is a legend in nanomedicine. He has pulled a lot of researchers from different institutions together to further the science.

This conference demonstrates to all of us that if we work together we can make a real improvement in patient survival,” she said.

Hamid Ghandehari, Ph.D., professor of pharmaceutics and bioengineering at the University of Utah, Salt Lake, has been involved in organizing past conferences and will co-host next year’s NanoDDS in Utah.

“This conference brings together scientists who work at the nano scale with a focus on targeted drug delivery,” he said.

Dr. Ghandehari, who also is director of the Utah Center for Nanomedicine and co-founder and co-director of the Nano Institute of Utah, said a Google search for nanomedicine in 2003 would have led to only a few hits.

“Ten years ago we hardly knew about how the shape of nanoparticles would affect distribution in the body,” he said. “The advances in nanotechnology since then have provided an opportunity for drug delivery scientists to more effectively deliver drugs to targeted sites.

“This conference helps move the science forward.”

Hamid Ghandehari, Ph.D., Professor of Pharmaceutics and Pharmaceutical Chemistry and Bioengineering of the University of Utah

Teruo Okano, Ph.D.

Polymer chemist Teruo Okano, Ph.D., professor and director of the Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Japan, said the NanoDDS symposium provides scientists inspiration for the future.

“At the conference, people, including active young researchers, aggressively ask questions. There is a lot of good discussion and that inspires me.

Sasha has shown us the importance of working with people from many disciplines. He has a clear vision for the future.”

Dr. Okano’s lab has developed new biomaterials called cell sheets to assist in reconstruction of the esophagus, corneal, heart and bladder.

31

INTERNATIONAL CONNECTIONS BUILD PROGRAM

A global community has developed at the CDDN, where students from all over the world come to study. From left: Yingchao Han, Ph.D., was recruited through the China Scholarship Council program; Anita Schulz, from the Dresden Technical University in Germany, worked on her master’s degree at the CDDN; and Masao Kamimura is from Japan.

Even before his 1994 arrival at UNMC, polymer chemist Alexander “Sasha” Kabanov, Ph.D., D.Sc., understood the importance of building international relationships.

While conducting research in the department of chemical enzymology at Moscow State University, he was invited into the laboratories of some of the most influential scientists in Japan, France, Germany and the United States.

So when the Soviet Union dissolved in 1991 and his research lost its state funding, a friend in Utah recommended that Dr. Kabanov seek a position at UNMC. The suggestion changed his life

and the life of many others these past 16 years as he created the Center for Drug Delivery and Nanomedicine (CDDN), an international, interdisciplinary drug delivery research center funded by more than $34 million in federal grants.

Yet, he never forgot how it felt to be an outsider.

“I found myself in a foreign country, where the people spoke a foreign language and had strange habits,” Dr. Kabanov said.

“My home is here now. In the CDDN labs, we speak many different languages (14) and I have built an international team

of people from 10 different countries. We want to change the world,” he said.

The Parke-Davis Professor in Pharmaceutics and director of the Center for Drug Delivery and Nanomedicine (CDDN) at UNMC is committed to expanding UNMC’s presence around the world.

“Nebraska can’t be isolated,” Dr. Kabanov said. “We have to think about the entire world because the health of this world effects our own.”

One of his personal measures of success is through the students who carry the knowledge of research conducted in the CDDN wherever they go.

“International collaboration in research and medical education has been one of our most important objectives.”

UNMC Chancellor Harold M. Maurer, M.D. To accomplish this he accepts graduate students and post docs from around the world and promotes student and faculty exchanges with Moscow State University, Russian State Medical University, Technical University of Dresden and the University of Tskuba in Japan.

Since 2005, 60 graduate students, post docs and visiting students from China, South Korea, Russia, India, Germany, Japan, Bangladesh, Denmark, France and Israel have studied at the CDDN. While American students have better communication skills, foreign students are better prepared to conduct research and have a stronger competitive edge, Dr. Kabanov said. “When UNMC students meet the best of the best from all over the world, they understand how tough the competition is on the global stage.”

Already, UNMC is a cosmopolitan campus where more than 60 different languages are spoken.

More than 15 percent of UNMC’s faculty, 600, graduated from international institutions, while 70 percent of post-doctoral students and 50 percent of graduate students are of international origin.

Global health is critically important, said UNMC Chancellor Harold M. Maurer, M.D. “We have to reach out. The populations of China, India and Russia are growing and developing into scientific powerhouses. Now is the time for UNMC to extend its influence.”

This is an opportunity for UNMC to expose students from Nebraska and foreign countries to different cultures and bring scientists together to collaborate on research, Dr. Maurer said.

“International collaboration in research and medical education

has been one of our most important objectives,” Dr. Maurer said. “One way we’ve chosen to meet this objective is by establishing friendships and connections through the exchange of graduate, medical and nursing students, as well as postdoctoral fellows, faculty members and administrators.”

The benefits for both parties in student and faculty exchanges are substantial. Forging partnerships with other countries not only advances scientific and economic growth, but promotes friendship and cultural understanding, he said.

“For UNMC to be a world-class institution, it needs to develop deep relationships with world-class partners to help shape the future of health care to better serve Nebraska and beyond,” Dr. Maurer said.

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World-wide collaborations In the past five years, UNMC has signed agreements with universities in Russia, China and Japan to allow for student and faculty exchanges and research collaborations.

Agreements have been made with Russian State Medical University, the nation’s largest medical school, Moscow State University, and four Japanese institutions — the University of Tsukuba, Tokyo Science University, Osaka University and RIKEN, a natural sciences research institution in Japan.

“These universities are home to some of the world’s best material scientists,” said Alexander “Sasha” Kabanov, Ph.D., D.Sc., professor in pharmaceutics and director of the Center for Drug Delivery and Nanomedicine (CDDN) at UNMC. Natasha Klyachko, Ph.D., D.Sc., a professor at Moscow State University and visiting professor to the CDDN, has continued to collaborate on projects with the group.

She worked with Dr. Kabanov to organize a weeklong nanomedicine school in Moscow in July 2009. Nearly 230 students from around the world attended the school that also was co-sponsored by Rusnano — a nanotechnology company owned by the Russian government.

“Interest in nanomedicine is high right now and we were fortunate to have Sasha and his team provide their expertise for the students,” Dr. Klyachko said.

The school in Moscow was the summer’s second for the CDDN, which also helped present a school in Lisbon, Portugal, that same time. The CDDN hosted a similar school in the summer of 2008 at UNMC. So far, nine students from Russia have trained in Omaha, and four more coming in August; two UNMC students have visited Moscow and more plan to come.

In 2008, Dr. Kabanov initiated a partnership between UNMC and four Japanese institutions.

From the partnership, Dr. Kabanov hopes to create a “materials medicine network,” a phrase he uses to describe the interface between materials science — such as chemistry and physics — and biological sciences and medicine.

Dr. Kabanov and others believe that by using nanoscience and engineering, materials medicine may lead to new drugs and treatments for many major health issues.

Combining their expertise with the biomedical expertise of UNMC investigators could lead to significant improvements in patient care and treatment on a global scale, said Yukio Nagasaki, Ph.D., of the University of Tsukuba, a partner institution.

Faculty members from the CDDN also have visited laboratories overseas as well. Tatiana Bronich, Ph.D., associate director of the CDDN and professor of pharmaceutical science, visited polymer chemist Teruo Okano, Ph.D., professor and director of the Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Japan.

“I’ve known Sasha since 1990 and recognized right away that he was a clever young researcher,” Dr. Okano said, noting that they have published a book together.

Students also are recruited through UNMC’s partnership with several Chinese universities and the China Scholarship Council program (CSC). The CSC selects the smartest students from the top 49 universities in China to send to top institutions around the world.

Don Leuenberger

UNMC has joined Harvard and Yale as one of 15 universities in the United States to collaborate with the CSC to develop joint programs between the two countries. UNMC is the only academic health science center in the group.

Don Leuenberger, UNMC vice chancellor for business and finance, says the CDDN under Dr. Kabanov’s leadership exemplifies world-class programs.

“They are programs of global reach and significance in which UNMC has a recognized leadership role. Dr. Kabanov deserves a lot of credit as his reputation globally as a nanomedicine expert has opened pathways to make the partnership possible,” he said.

Courtney Fletcher, Pharm.D., dean of the College of Pharmacy, is excited about the partnerships. “These collaborations make our world of research smaller and allow us to advance science in a much more comprehensive approach.”

Courtney Fletcher, Pharm.D.,

University of Nebraska expands its horizons New international initiatives exist on each of the University of Nebraska campuses, and international engagement is one of the major goals of the University of Nebraska Foundation’s “Unlimited Possibilities” campaign, said NU President James B. Milliken.

One major goal is to double international student enrollment on NU campuses by 2019. This year, 136 countries are represented in the 3,018 international students enrolled on all four campuses. UNMC has 521 international students from 63 countries.

“International students add millions to the state’s economy, but the real value is in the richness of the experience gained by having students from around the world on our campuses and in our communities,” Milliken said.

James B. Milliken

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University of Nebraska Medical Center 985830 Nebraska Medical Center Omaha, Nebraska 68198-5830

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One of the first centers in the world dedicated to nanotechnology research in medicine, the Center for Drug Delivery and Nanomedicine (CDDN) has grown to support 33 faculty members. And, with more $34 millions in research support at UNMC, CDDN scientists are closer on providing cures that once were deemed impossible.

Breakthroughs for life.

unmc.edu