This octadentate HOPO is a sequestering agent that can encapsulate actinides, such as this plutonium atom (gold), into tightly bound cage-like complexes for excretion out of the body. Image by Zosia Rostomian, Berkeley Lab |
The
New York Times recently reported that in the darkest moments of the
triple meltdown last year of the Fukushima Daiichi nuclear power plant,
Japanese officials considered the evacuation of the nearly 36 million
residents of the Tokyo metropolitan area. The consideration of so
drastic an action reflects the harsh fact that in the aftermath of a
major radiation exposure event, such as a nuclear reactor accident or a
“dirty bomb” terrorist attack, treatments for mass contamination are
antiquated and very limited. The only chemical agent now available for
decontamination—a compound known as DTPA—is a Cold War relic that must
be administered intravenously and only partially removes some of the
deadly actinides—the radioactive chemical elements spanning from
actinium to lawrencium on the periodic table—that pose the greatest
health threats.
Scientists
at the U.S. Department of Energy (DOE)’s Lawrence Berkeley National
Laboratory (Berkeley Lab) are developing a much more effective
alternative that decontaminates a large number of the actinides likely
to be part of the radiation exposure from a nuclear plant or weapon,
including plutonium, americium, curium, uranium and neptunium.
Furthermore, the Berkeley Lab treatment can be administered orally in
the form of a pill, a necessity for prompt treatment in the event of
mass contamination. Depending on the level of radiation exposure and how
soon treatment can start, one of these pills would result in the
excretion of approximately 90% of the actinide contaminants within 24
hours. Taking one pill daily for two weeks should be enough to remove
virtually all of the actinide contaminants.
“With
the expanding use of nuclear power and unfortunate possibility of
nuclear weapon use, there is an urgent need to develop and implement an
improved therapy for actinide contamination of a large population,” says
Rebecca Abergel, a chemist who leads the Bioactinide Group at Berkeley
Lab’s Glenn T. Seaborg Center. “We are now in the process of
demonstrating that our actinide-specific decontaminating agents are
ready for clinical development.”
Once
actinides are ingested or inhaled, their radioactivity and cancerous
interactions with cells and tissue demand they be immobilized and
removed from the body as soon as possible.
Abergel
and her group are part of an effort at Berkeley Lab that began more
than two decades ago under the leadership of Ken Raymond, a chemist who
holds joint appointments with Berkeley Lab and the University of
California (UC) Berkeley, where he is the Chancellor’s Professor of
Chemistry, in collaboration with the late Patricia Durbin. The primary
goal of this project has been to identify sequestering agents that can
encapsulate actinides into tightly bound cage-like chemical complexes
for transport out of the body. The early focus of this research was on
plutonium, the alpha particle-emitting actinide discovered by Berkeley
Lab Nobel laureate Glenn Seaborg, and natural chelators, the crablike
molecules that specifically bind with iron and other metal ions.
“Since
the biochemical properties of plutonium(IV) and iron(III) are similar,
we modeled our sequestering agents after the chelating unit found in
siderophores,” Raymond says.
Siderophores
are small molecules secreted by bacteria to extract and solubilize
iron. “This biomimetic approach enabled us to design multidentate
hydroxypyridonate ligands that are unrivaled in terms of
actinide-affinity, selectivity and efficiency.”
The
two best candidate hydroxypyridonate ligands—nicknamed HOPO—developed
by Abergel and her colleagues are a tetradentate, which has four
chelating arms, and an octadentate, which has eight chelating arms. The
“arms” in this case are atoms with pairs of electrons available for
covalent bonding with an actinide.
Rebecca Abergel is the leader of the Bioactinide Group at Berkeley Lab’s Glenn T. Seaborg Center, where a safe, effective radiation decontamination treatment is being developed. Photo by Roy Kaltschmidt, Berkeley Lab |
“We’ve
advanced our two candidate ligands through the initial phases of
pre-clinical development by successfully scaling up synthesis to the
5-kg level and establishing baseline preparation and analytical methods
suitable for manufacturing larger amounts under good manufacturing
practice guidelines,” Abergel says.
The
team has also carried out extensive studies in animal models and human
cell lines that established the two HOPO candidates as being highly
effective and non-toxic at the tested doses. As for comparisons between
the two, each has its own merits.
“A
single octadentate HOPO can form a full actinide complex and results in
more total actinide excretion,” Abergel says. “However, it is easier
for the smaller tetradentate HOPO to pass through biological membranes
and access desired target sites in the body. Both warrant further
development for emergency use in the case of a radiological event.”
Abergel
says the basic research and development phase of these two candidates
has been completed and she and her group have started the process with
the U.S. Food and Drug Administration (FDA) to determine what further
data is needed to move into clinical trials. Typically at this stage of
development a private pharmaceutical company would step in but it is
difficult to attract private investors for a drug that will hopefully
never be needed.
“As
we move further along with the FDA process it should be easier to
convince private pharmaceutical companies to get involved,” Abergel
says.
In
addition to Abergel, Raymond and Durbin, other researchers who are or
have been involved in this project include Dahlia An, Kathleen
Bjornstad, Eleanor Blakely, Deborah Bunin, Polly Chang, Shirley Ebbe,
Erin Jarvis, Birgitta Kullgren, Chris Rosen, David Shuh, Manuel
Sturzbecher-Hoehne and Jide Xu.
There
have been several scientific papers published about this work with the
most recent being “Multidentate terephthalamidate and hydroxypyridonate
ligands: towards new orally active chelators,” in the journal Hemoglobin. It was written by Abergel and Raymond.
This
research was primarily supported by the National Institutes of Health
through the National Institute of Allergy and Infectious Diseases and
the Rapid Access to Interventional Development Program. Support also
came from the DOE Office of Science.
Multidentate terephthalamidate and hydroxypyridonate ligands: towards new orally active chelators
