Under Magnetic Force, Nanoparticles May Deliver Gene Therapy

[Just a man]

ZZ:www.sciencedaily.com/.../06/070613153205.htm

ScienceDaily (Aug. 1, 2007) -- 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.