Tissue
deprived of oxygen (ischemia) is a serious health condition that can
lead to damaged heart tissue following a heart attack and, in the case
of peripheral arterial disease in limbs, amputation, particularly in
diabetic patients.
Northwestern
University researchers have developed a novel nanostructure that
promotes the growth of new blood vessels and shows promise as a therapy
for conditions where increased blood flow is needed to supply oxygen to
tissue.
“An
important goal in regenerative medicine is the ability to grow blood
vessels on demand,” said Samuel I. Stupp, Board of Trustees Professor of
Chemistry, Materials Science and Engineering, and Medicine. “Enhancing
blood flow at a given site is important where blood vessels are
constricted or obstructed as well as in organ transplantation where
blood is needed to feed the cells properly.”
Stupp led the study that will be published the week of Aug. 1 by the Proceedings of the National Academy of Sciences (PNAS).
Stupp
and his team designed an artificial structure that, like the natural
protein it mimics, can trigger a cascade of complex events that promote
the growth of new blood vessels. The protein the nanostructure mimics is
called vascular endothelial growth factor, or VEGF.
The
nanostructure, however, exhibits important advantages over VEGF: it
remains in the tissue where it is needed for a longer period of time; it
is easily injected as a liquid to the tissue; and, relative to the
protein, it is inexpensive to produce. (VEGF was tested in human
clinical trials but without good results, possibly due to it remaining
in the tissue for only a few hours.)
“One
of the major challenges in the field of ischemic tissue repair is
sustained delivery of therapeutic agents to target tissue,” said Douglas
W. Losordo, M.D., a co-author of the paper and director of
Northwestern’s Feinberg Cardiovascular Research Institute. “Native VEGF
has a very short tissue half-life, limiting its potency and requiring
repeat dosing. By virtue of its engineering, this nanomaterial mimics
VEGF but is capable of much longer life in the tissue, greatly enhancing
its potency.”
Losordo
also is the Eileen M. Foell Professor of Heart Research at
Northwestern’s Feinberg School of Medicine and director of the Program
in Cardiovascular Regenerative Medicine at Northwestern Memorial
Hospital.
“We
approached this as an engineering problem,” said first author Matthew
Webber, a doctoral student in Stupp’s research group at the Institute
for BioNanotechnology in Medicine (IBNAM).
“To be able to design and create a small molecule that can assemble
into nanostructures that function therapeutically is rewarding.”
Stupp
and his team created a nanostructure in the form of a fiber that
displays on its surface a high density of peptides (potentially hundreds
of thousands) per fiber. The peptides mimic the biological effect of
VEGF, initiating the signaling process in cells that leads to blood
vessel growth.
The
extremely large number of active peptides results in a very potent
therapeutic, and the size and stability of the nanofiber ensure the
structure is retained longer in the tissue after injection.
After developing the nanostructure, Stupp and Webber teamed up with Losordo to test the nanostructures in vivo.
The
researchers used an animal model of peripheral arterial disease and
demonstrated the effectiveness of the nanofiber in treating the
condition. In animals whose limbs were restricted to only 5 to 10
percent of normal blood flow, treatment with the nanofiber resulted in
blood flow being restored to 75 to 80 percent of normal levels.
Treatment
with the peptide alone did not produce the same therapeutic effect; the
nanostructure was needed to display the peptides to produce results.
“Using
simple chemistry, we have produced an artificial structure by design
that can trigger complex events,” said Stupp, who is director of IBNAM.
“Our nanostructure shows the promise of a general approach to mimicking
proteins for broader use in medicine and biotechnology.”
The researchers next plan to investigate the protein mimic in a heart attack animal model.
The National Institutes of Health supported the research.
