ARBOR, Mich.---University of Michigan researchers
have developed a faster, more efficient way to produce
a wide variety of nanoparticle drug delivery systems,
using DNA molecules to bind the particles together.
dendrimers can be assembled in many configurations
by using attached lengths of single-stranded DNA molecules,
which naturally bind to other DNA strands in a highly
this approach, you can target a wide variety of molecules---drugs,
contrast agents---to almost any cell," said Dr.
James R. Baker Jr., the Ruth Dow Doan Professor of
Nanotechnology and director of the Center for Biologic
Nanotechnology at U-M.
complexes can be specifically targeted to cancer cells
and are small enough to enter a diseased cell, either
killing it from within or sending out a signal to
identify it. But making the particles is notoriously
difficult and time-consuming.
nanoparticle system used by Baker's lab is based on
dendrimers, star-like synthetic polymers that can
carry a vast array of molecules on the ends of their
arms. It is possible to build a single dendrimer carrying
many different kinds of molecules such as contrast
agents and drugs, but the synthesis process is long
and difficult, requiring months for each new molecule
added to the dendrimer in sequential steps. And the
yield of useful particles drops with each successive
step of synthesis.
a paper published Jan. 21 in the journal Chemistry
and Biology, U-M Biomedical Engineering graduate student
Youngseon Choi built nanoparticle clusters of two
different functional dendrimers, one designed for
imaging and the other for targeting cancer cells.
Each of the dendrimers also carried a single-stranded,
non-coding DNA synthesized by Choi.
a solution of two different kinds of single dendrimers,
these dangling lengths of DNA, typically 34-66 bases
long, found complementary sequences on other dendrimers
and knitted together, forming barbell shaped two-dendrimer
complexes with folate on one end and fluorescence
on the other end.
receptors are over-expressed on the surface of cancer
cells, so these dendrimer clusters would tend to flock
to the diseased cells. The other end of the complex
carries a fluorescent protein so that the researchers
can track their movement.
series of experiments using cell sorters, 3-D microscopes
and other tools verified that these dendrimers hit
their targets, were admitted into the cells and gave
off their signaling light. The self-assembled dendrimer
clusters were shown to be well formed and functional.
is the proof-of-concept experiment," Choi said.
But now that the assembly system has been worked out,
other forms of dendrimer clusters are in the works.
you wanted to make a therapeutic that targeted five
drugs to five different cells, it would be 25 synthesis
steps the traditional way," Baker said. At two
to three months per synthesis, and a significant loss
of yield for each step, that approach just wouldn't
the Baker group will create a library of single-functional
dendrimers that can be synthesized in parallel, rather
than sequentially, and then linked together in many
different combinations with the DNA strands.
it's like having a shelf full of Tinker Toys,"
array of single-functional dendrimers, such as targets,
drugs, and contrast agents, and the ability to link
them together quickly and easily in many different
ways would enable a clinic to offer 25 different "flavors"
of dendrimer with only ten synthesis steps, Baker
foresees a nanoparticle cluster in which a single
dendrimer carries three single-strands of DNA, each
with a sequence specific to the DNA attached to other
kinds of dendrimers. Put into solution with these
other tinker toys, the molecule would self-assemble
into a four-dendrimer complex carrying one drug, one
target, and one fluorescent.
more information, visit: Nanotechnology in the Life
for Biologic Nanotechnology---http://nano.med.umich.edu
and Biology journal---http://www.chembiol.com
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