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As the field of nanomedicine matures, an emerging point of contention has
been what shape nanoparticles should be to deliver their drug or DNA payloads
most effectively.
A pair of new papers by scientists at The Methodist Hospital Research
Institute (TMHRI) and six other institutions suggests these microscopic
workhorses ought to be disc-shaped, not spherical or rod-shaped, when targeting
cancers at or near blood vessels.
“The vast majority—maybe 99%—of the work being done right now is using
nanoparticles that are spherical,” said TMHRI biomedical engineer Paolo
Decuzzi, PhD, principal investigator for both projects. “But evidence is
showing there may be better ways to get chemotherapy drugs to the site of a
vascularizing cancer.”
Despite their popularity, there are problems with sphere-shaped
nanoparticles. They’re small, and can’t deliver a lot of drugs when they
finally reach their targets. And they’re also more likely to get pushed
downstream by blood’s powerful flow.
“The small surface exposed by spherical nanoparticles to the blood
vessel walls—theoretically a single point—in the tumor tissue cannot support
stable, firm adhesion and they are easily washed away. And this hampers their
effective accumulation within the diseased tissue,” Decuzzi said. “So
a number of laboratories have been asking, how can we maximize the accumulation
of nanoparticles in the diseased tissues? Is there a better shape?”
In Biomaterials, Decuzzi and
coauthors show that at different, biologically relevant flow speeds,
disc-shaped nanoparticles were less likely to get pushed off their targets than
rod-shaped nanoparticles—another shape previously proposed as an alternative to
spheres. The ideal size was 1,000 by 400 nm. The experiments were conducted in vitro and confirmed by computational
modeling.
Spherical nanoparticles are built around the drug payload in a free, 3D
fashion through self-assembly. The particle grows uniformly in all directions,
forming a spherical—or nearly spherical—nanoparticle.
The Methodist nanomedicine group, led by TMHRI President and CEO Mauro
Ferrari, PhD, has developed a completely different technique. Disc-shaped
nanoparticles are created with photolithographic technology, the same tools
used to make the tiniest components in computers. Photolithography allows
Ferrari, Decuzzi, and colleagues to specify the size, shape, and surface
properties of the nanoparticles with a great deal of accuracy. The
nanoparticles are built with sponge-like holes through them, which is where the
drugs are loaded.
“We can change the size, shape, and surface properties—’3S’ parameters—of
the particles independently,” Decuzzi said. “It is a very powerful
technique.”
The nanoparticles are built with silicon, and biologically relevant
molecules are later attached to the outside to improve binding to target cells
and to delay destruction by the immune system. Silicon has an extremely low
toxicity profile at the doses typically used in humans and animal models.
Decuzzi said silicon nanoparticles are readily broken down and removed from the
body within 24 to 48 hrs.
The second paper published by Decuzzi and colleagues, in the Journal of Controlled Release, used
mouse models to show that 1,000 by 400 nm disc-shaped nanoparticles bind
readily to and near melanoma cells, at 5% to 10% of the injected dose per gram organ—concentrations
that are competitive with or better than those previously reported for spheroid
nanoparticles. The researchers also showed 1,000 by 400 nm discs were least
likely (than smaller or larger discs, or rods) to end up in the liver.
“These two papers are the culmination of eight years of work, looking
at the properties of disc-, rod-, and spherical nanoparticles in computer
simulations, in vitro, and then in vivo,” Decuzzi said. “What
has been most rewarding is that all the important things we predicted via
mathematical models turned out to be true in real-life experiments. We are
getting close to answering crucial questions about what these nanoparticles
need to look like.”
Decuzzi says his group will continue working on the optimization of
nanoparticles and, in particular, will be looking at what he calls the
“4S” problem. After establishing the right size, shape, and surface
chemistry, Decuzzi says he wants to see if the right amount of stiffness, or
flexibility, can further enhance the in
vivo performance of nanoparticles.
Source: The Methodist Hospital System
