nano10-9 an annual publication of CDDN

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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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14
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nano10-9 an annual publication of CDDN
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nano
2011
nano
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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.
6
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
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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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CONTENTS
DRUGS DESIGNED TO “GO RAMBO” IN
PANCREAS CANCER CELLS
8
12
BIOIMAGING CORE LABORATORY PROVIDES
CRITICAL SUPPORT
13
NANOMATERIALS CORE LABORATORY
PROVIDES NANOMATERIAL DEVELOPMENT
AND CHARACTERIZATION
ROLE OF INFLAMMATION IS EXAMINED IN
TRAUMATIC BRAIN INJURY RESEARCH
3
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.
5
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
7
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
9
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
11
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.
13
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 processis 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.”
15
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 tozhe 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 Washington
University, 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. Lowe’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 CNND 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 students’ 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.
33
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 4 more
comming 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
35
nano
University of Nebraska Medical Center
985830 Nebraska Medical Center
Omaha, Nebraska 68198-5830
o
-9
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