A nanoparticle developed at Rice University and tested in
collaboration with Baylor College of Medicine (BCM) may bring great benefits to
the emergency treatment of brain-injury victims, even those with mild injuries.
Combined polyethylene glycol-hydrophilic carbon clusters
(PEG-HCC), already being tested to enhance cancer treatment, are also adept
antioxidants. In animal studies, injections of PEG-HCC during initial treatment
after an injury helped restore balance to the brain’s vascular system.
The results were reported in ACS Nano.
A PEG-HCC infusion that quickly stabilizes blood flow in the
brain would be a significant advance for emergency care workers and battlefield
medics, says Rice chemist and co-author James Tour.
“This might be a first line of
defense against reactive oxygen species (ROS)
that are always overstimulated during a medical trauma, whether that be to an
accident victim or an injured soldier,” says Tour, Rice’s T.T. and W.F.
Chao Chair in Chemistry as well as a professor of mechanical engineering and
materials science and of computer science. “They’re certainly exacerbated when
there’s trauma with massive blood loss.”
In a traumatic brain injury, cells release an excessive
amount of an ROS known as superoxide (SO) into the blood. Superoxides are toxic
free radicals, molecules with one unpaired electron, that the immune system
normally uses to kill invading microorganisms. Healthy organisms balance SO
with superoxide dismutase (SOD), an enzyme that neutralizes it. But even mild
brain trauma can release superoxides at levels that overwhelm the brain’s
natural defenses.
“Superoxide is the most deleterious of the reactive oxygen
species, as it’s the progenitor of many of the others,” Tour says. “If you
don’t deal with SO, it forms peroxynitrite and hydrogen peroxide. SO is the
upstream precursor to many of the downstream problems.”
SO affects the autoregulatory mechanism that manages the
sensitive circulation system in the brain. Normally, vessels dilate when blood
pressure is low and constrict when high to maintain an equilibrium, but a lack
of regulation can lead to brain damage beyond what may have been caused by the
initial trauma.
“There are many facets of brain injury that ultimately
determine how much damage there will be,” says Thomas Kent, the paper’s
co-author, a BCM professor of neurology and chief of neurology at the Michael
E. DeBakey Veterans Affairs Medical Center in Houston. “One is the initial
injury, and that’s pretty much done in minutes. But a number of things that
happen later often make things worse, and that’s when we can intervene.”
Kent cited as an example the second burst of free radicals
that can occur after post-injury resuscitation. “That’s what we can treat: the
further injury that happens because of the necessity of restoring somebody’s
blood pressure, which provides oxygen that leads to more damaging free
radicals.”
In tests, the researchers found PEG-HCC nanoparticles
immediately and completely quenched superoxide activity and allowed the
autoregulatory system to quickly regain its balance. Tour says ROS molecules
readily combine with PEG-HCCs, generating “an innocuous carbon double bond, so
it’s really radical annihilation. There’s no such mechanism in biology.” While
an SOD enzyme can alter only one superoxide molecule at a time, a single
PEG-HCC about the size of a large protein at 2 to 3
nm wide and 30 to 40 nm long can quench hundreds or thousands. “This is
an occasion where a nano-sized package is doing something that no small drug or
protein could do, underscoring the efficacy of active nano-based drugs.”
“This is the most remarkably effective thing I’ve ever
seen,” Kent says. “Literally within minutes of injecting it, the cerebral blood
flow is back to normal, and we can keep it there with just a simple second
injection. In the end, we’ve normalized the free radicals while preserving
nitric oxide (which is essential to autoregulation).
These particles showed the antioxidant mechanism we had previously identified as
predictive of effectiveness.”
The first clues to PEG-HCC’s antioxidant powers came during
nanoparticle toxicity studies with the MD Anderson Cancer Center. “We noticed
they lowered alkaline phosphatase in the liver,” Tour says. “One of our Baylor
colleagues saw this and said, ‘Hey, this looks like it’s actually causing the
liver cells to live longer than normal.'”
“Oxidative destruction of liver cells is normal, so that got
us to thinking these might be really good radical scavengers,” Tour says.
Kent says the nanoparticles as tested showed no signs of
toxicity, but any remaining concerns should be answered by further tests. The
researchers found the half-life of PEG-HCCs in the blood—the amount of time it
takes for half the particles to leave the body—to be between two and three
hours. Tests with different cell types in
vitro showed no toxicity, he says.
The research has implications for stroke victims and organ
transplant patients as well, Tour says.
Next, the team hopes to have another lab replicate its
positive results. “We’ve repeated it now three times, and we got the same
results, so we’re sure this works in our hands,” Kent says.
Source: Rice University
Filed Under: Drug Discovery
