EVANSTON, Ill. --- In the fight against cancer, antisense drugs, which prevent
genes from producing harmful proteins such as those that cause cancer, have
the promise to be more effective than conventional drugs, but the pace of development
of these new drugs has been slow.
Using gold nanoparticles combined with DNA, scientists
at Northwestern University now have demonstrated
a new method for developing antisense drugs that
outperform conventional antisense agents. The findings
will be published May 19 in the journal Science.
A major challenge has been delivering antisense
drugs to cells inside the body while avoiding their
break down along the way. The Northwestern team shows
that by attaching multiple strands of antisense DNA
to the surface of a gold nanoparticle (forming an "antisense
nanoparticle") the DNA becomes more stable and can
bind to the target messenger RNA (mRNA) more effectively
than DNA that is not attached to a nanoparticle surface
(as in commercial agents).
When compared to antisense DNA complexed with commercial
agents such as Lipofectamine and Cytofectin, the
antisense nanoparticles were more effective in gene
knockdown (decreasing gene expression and protein
production), were less susceptible to degradation
resulting in longer lifetimes, exhibited lower toxicity
and were more readily absorbed by cells, exhibiting
a greater than 99 percent uptake.
"When mutations in the body's genetic material cause
too many copies of certain proteins, cancer and other
diseases can result," said Chad A. Mirkin, director
of Northwestern's Center for Cancer Nanotechnology
Excellence, who led the study. "Whereas typical drugs
target the proteins, it is possible through gene
therapy to target the genetic material itself before
it is ever made into copies of harmful proteins.
One way to target the genetic material is to block
the messenger RNA by using 'antisense DNA,' which
prevents the message from ever becoming a protein."
Once inside cells, the DNA-modified nanoparticles
act as messenger RNA "sponges" that bind to their
targets and prevent them from being converted into
In their experiments the researchers targeted mRNA
sequences that code for enhanced green fluorescent
protein (EGFP) expressed in a mouse cell. The antisense
sequence of the DNA attached to the nanoparticles
was complementary to the mRNA for EGFP expression.
When the nanoparticles were introduced to the cells
the fluorescence dimmed -- a result of the nanoparticles
binding to the mRNA and shutting down the protein's
expression, or fluorescence.
"In the future, this exciting new class of antisense
material could be used for the treatment of cancer
and other diseases that have a genetic basis," said
Mirkin, who is George B. Rathmann Professor of Chemistry,
professor of medicine and professor of materials
science and engineering.
In addition to Mirkin, other authors on the Science
paper are Nathaniel L. Rosi (co-first author), David
A. Giljohann (co-first author), C. Shad Thaxton,
Abigail K. R. Lytton-Jean and Min Su Han, all from