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A mixture of current drugs and carbon nanoparticles shows potential to
enhance treatment for head and neck cancers, especially when combined with
radiation therapy, according to new research by Rice
University and the University of Texas MD
Anderson Cancer Center.
The work blazes a path for further research into therapy customized to the
needs of individual patients. The therapy uses carbon nanoparticles to
encapsulate chemotherapeutic drugs and sequester them until they are delivered
to the cancer cells they are meant to kill.
A paper on the research was published in ACS
Nano.
The new strategy by Rice chemist James Tour and Jeffrey Myers, a professor
of head and neck surgery at MD Anderson, combines paclitaxel (PTX) and Cetuximab
(Cet) with hydrophilic carbon clusters functionalized with polyethylene glycol,
known as PEG-HCC.
Cetuximab, the targeting agent, is a humanized monoclonal antibody that
binds exclusively to the epidermal growth factor receptor (EGFR), a
cell-surface receptor overexpressed by 90% of head and neck squamous cell
cancers. Paclitaxel, an active agent in chemotherapy, is used to treat lung,
ovarian, breast, and head and neck cancers. In combination, they have the
ability to target and attack cancerous cells.
Because paclitaxel is hydrophobic—it won’t mix with water—the substances are
generally combined with Cremophor EL, a castor oil-based carrier that allows
the compound marketed as Taxol to be delivered intravenously to patients.
Tour, Myers, and their associates have found a simple way to mix PTX and
Cetuximab with carbon clusters that adsorb the active ingredients. The new
compound is water-soluble and is more effective at targeting tumors than Taxol
while avoiding the toxic effects of paclitaxel and Cremophor on adjacent
healthy cells, they wrote.
“It’s very common to administer cortical steroids to limit the allergic
response to Cremophor EL,” said 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.
Tour said the Cet/PTX/PEG-HCC elements combine easily. “We show in the
paper that when we take paclitaxel up in our hydrophilic carbon clusters, we
can deliver these just as well as commercial Taxol.
“But you can never break into a market with something that’s just as
good as what’s already out there. You have to be substantially better. The
beauty of what we’re doing is that we can potentially use a much smaller amount
of the drug for chemotherapy. Just eliminating the Cremophor is a real
advantage,” he said.
Tour noted a recently approved chemotherapy drug that combines paclitaxel
with albumin nanoparticles, Abraxane, also shows promise. “That works
well, but it still only has about 10% of the market after six or seven years of
use,” he said.
Myers, the Hubert L. and Olive Stringer Distinguished Professor in Cancer
Research at MD Anderson, said combining Cet/PTX/PEG-HCC and radiation therapy
in tests on mice showed a significant boost in killing tumors. “Our
hypothesis is that PTX, the chemotherapy drug, sensitizes the cancer cells to
the effects of radiation and the Cetuximab/PEG-HCC increases the delivery of
PTX to the cancer cells,” he said.
Unlike Cremophor, Tour said, the enhanced carbon clusters are nontoxic.
Biodistribution and toxicity studies showed the “large majority” of
PEG-HCCs are excreted through the kidneys, while trace amounts in the livers
and spleens of mice tested showed no damage to the organs.
The strategy sprang from conversations between Tour and Rice chemist and
Nobel laureate Richard Smalley, who died of leukemia in 2005. “I was
sitting with Rick at MD Anderson while he was being treated, and we got to
talking about using carbon particles for delivery as carbon-based carriers.
“But we had nothing specific,” Tour said. “I started to work
on this without funding, and shortly after Rick’s passing in October 2005, I
met with Jeff Myers.”
“I wanted to establish a multidisciplinary program to study
nanoparticle-based therapeutics for cancer in general, and more specifically,
head-and-neck cancer,” Myers said. “At the time, Dr. Garth Powis
(professor and chair of the Department of Experimental Therapeutics at MD
Anderson) directed me to Dr. Mauro Ferrari (now president of The Methodist
Hospital Research Institute and an adjunct professor of bioengineering at
Rice), who ultimately put me in touch with Dr. Tour.
“His enthusiasm for science and willingness to further explore the
potential of carbon nanoparticles to treat cancer patients was apparent right
away, and we launched a collaborative effort that has been quite
productive,” he said.
Myers is pleased with what the team has accomplished so far. “This
collaborative work has ‘proved the principle’ that carbon nanoparticles can be
used to non-covalently link a chemotherapeutic drug with a targeting antibody
that can deliver the drug specifically to a cancer cell,” he said.
“This principle could be used to deliver other drugs to other types of
cells through specific targeting of cell surface receptors as a method of
increasing the therapeutic ratio.
“Though I am not an expert in these other areas, this could potentially
have applications in infectious diseases, neurologic disorders and
cardiovascular illnesses,” he said.
Tour sees potential for clinical uses of PEG-HCCs for brain cancer and
traumatic brain injuries as well as chemotherapy, but acknowledged the
introduction of such drugs for human use is a long way off. “To get a drug
through all the different phases, including trials, typically takes 12 to 14
years and about $1.25 billion,” he said. “That can sometimes be
expedited through experimental trials with patients who have no other options,
but it’s still a long and expensive haul.”
Still, he said the new work is a strong step in the right direction.
“This paper is the highlight of six years of research,” he said.
“It all came together. This is the crescendo, right here.”
