After binding DNA
segments to tiny iron-containing spheres called nanoparticles, researchers
have used magnetic fields to direct the nanoparticles into arterial muscle
cells, where the DNA could have a therapeutic effect. Although the
research, done in cell cultures, is in early stages, it may represent a new
method for delivering gene therapy to benefit blood vessels damaged by
arterial disease.
The nanoparticles are extremely small, ranging from 185 to 375
nanometers (a nanometer is one billionth of a meter, or a millionth of a
millimeter). For comparison, red blood cells are ten to 100 times larger.
The researchers were able to control the nanoparticle size by varying the
amount or composition of solvents they used to form the nanoparticles.
The magnetically driven delivery system also may find broader use as a
vehicle for delivering drugs, genes or cells to a target organ. "This is a
novel delivery system, the first to use a biodegradable, magnetically
driven polymer to achieve clinically relevant effects," said study leader
Robert J. Levy, M.D., the William J. Rashkind Chair of Pediatric Cardiology
at The Children's Hospital of Philadelphia. "This system has the potential
to be a powerful tool."
The proof-of-principle study, performed on vascular cells in culture,
appears in the August issue of the FASEB Journal, published by the
Federation of American Societies for Experimental Biology.
Impregnated with iron oxide, the nanoparticles carry a surface coating
of DNA bound to an organic compound called polyethylenimine (PEI). The PEI
protected the DNA from being broken down by enzymes called endonucleases
that were present in the cell cultures and which occur normally in the
bloodstream.
The DNA was in the form of a plasmid, a circular molecule that here
carried a gene that coded for a growth-inhibiting protein called
adiponectin. By applying a magnetic field, the study team steered the
particles into arterial smooth muscle cells. Inside each cell, the DNA
separated from the particle, entered the cell nucleus, and produced enough
adiponectin to significantly reduce the proliferation of new cells.
In a practical application, such nanoparticles could be magnetically
directed into stents, the tiny, expandable metal scaffolds inserted into a
patient's partially blocked vessels to improve blood flow. Many stents
eventually fail as cells grow on their surfaces and create new
obstructions, so delivering anti-growth genes to stents could help keep
blood flowing freely.
The materials composing the nanoparticles are biodegradable, so they
break down into simpler, nontoxic chemicals that can be carried away in the
blood. "Previous researchers had shown that magnetically driven
nanoparticles could deliver DNA in cell cultures, but ours is the first
delivery system that is biodegradable, and therefore, safer to use in
people," said Levy.
"This delivery system may be a useful tool for delivering nonviral gene
therapy, because it efficiently binds and protects DNA in blood serum and
delivers it to cells," added Levy. As a nonviral method, it avoids the
unwanted immune system responses that have occurred when viruses are used
to deliver gene therapy.
Levy said his team would pursue further studies into the feasibility of
using the nanoparticles for gene therapy in blood vessels damaged by
vascular disease. He suggested that the nanoparticles might find broader
application, such as delivering gene therapy to tumors, or carrying drugs
instead of or in addition to genes. Another possibility is that after
preloading genetically engineered cells with nanoparticles, researchers
could use magnetic forces to direct the cells to a target organ.
Furthermore, researchers might deliver nanoparticles to magnetically
responsive, removable stents in sites other than blood vessels, such as
airways or parts of the gastrointestinal tract. "We could remove the stent
after the nanoparticles have delivered a sufficient number of genes, cells
or other agents to have a long-lasting benefit," he added.
Financial support for the study came from the National Institutes of
Health, the Nanotechnology Institute and the William J. Rashkind Endowment
of The Children's Hospital of Philadelphia. Dr. Levy's co-authors were
Michael Chorny, Ph.D., Boris Polyak, M.D., and Ivan S. Alferiev, Ph.D., of
Children's Hospital; Kenneth Walsh, of the Whitaker Cardiovascular
Institute of the Boston University School of Medicine; and Gary Friedman,
of Drexel University School of Biomedical Engineering and Health Sciences,
Philadelphia.
About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit chop.
The Children's Hospital of Philadelphia
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