Designing nanosize molecules that seek out and infiltrate
Rod Balhorn, a biochemist at Lawrence Livermore National Laboratory, has always been fascinated
with biological molecules and their surfaces. Their complex, convoluted structures determine which other
molecules they will interact with among the thousands they encounter as they carry out their various functions.
"What if I could design molecules to interact in ways that I decide are important?" Balhorn
often wondered. "What if I could create something that seeks out, recognizes, and sticks to the surface
of a toxin, for instance, then destroys it?"
With the help of computer technology, biochemical manipulations and plain old trial and error, this sci-fi
scenario is becoming a reality. With his collaborators at Lawrence Livermore and UC Davis Cancer Center,
Balhorn has constructed unimaginably tiny molecules. He calls them SHALs (for synthetic high-affinity
ligands). And his novel creations are beginning to show promise.
SHALs have a diameter of three to four nanometers (a nanometer is one-billionth of a meter). A virus,
in comparison, is an ungainly 30 to 50 nanometers wide. To put this infinitesimally small scale in context,
the distance between two lines of a fingerprint is about 80,000 nanometers.
SHALs are an example of nanotechnology, a young field that may have far-reaching implications for cancer.
SHALs are among the most exciting results to emerge so far from the pioneering partnership between the
UC Davis Cancer Center and Lawrence Livermore National Laboratory, in which scientists are turning biodefense
technology into a new cancer offense.
Balhorn originally conceived of SHALs as a way to thwart bioterrorism. He wanted to design molecules
to bind to potential bioterror agents like botulism or anthrax, in order to quickly and efficiently detect
and neutralize them.
But it wasn't long before the biochemist envisioned medical applications for his technology. "When
I attended meetings with UC Davis Cancer Center researchers," he says, "I saw the potential
of SHALs to fit their needs."
Prostate cancer weapon?
One cancer researcher excited about this potential is Hsing-Jien Kung, deputy director of the UC Davis
Cancer Center and director of its basic science program.
Kung's research focuses on the androgen receptors on the surface of prostate cancer cells. When these
receptors are "activated," they go into high gear, resulting in rapid cancer growth and a poor
prognosis for the patient. But distinguishing this activated form of the disease from less aggressive
prostate cancer has always been problematic.
Enter Balhorn and his SHAL toolkit. Based on knowledge of the conformational structure of the activated
receptor, Balhorn can design a SHAL that will bind to it. Attached to a fluorescent tag, the SHAL can
lock onto activated androgen receptors and alert Kung that they are present in the prostate cancer cell.
Tiny Trojan horses
The work is still in its initial phases, but Kung is optimistic about its potential. "SHALs may
be able to help a clinician predict whether a cancer needs aggressive therapy before it grows out of control,"
Kung says. "This is a remarkable technology with far-reaching applications that no other current
Kung also hopes SHALs may be used to fight prostate cancer directly. By competing with the androgens
(male hormones) that would otherwise bind to activated receptors, Balhorn's SHALs may block the signal
for more rapid cell growth and thereby inhibit the cancer.
Most cancer treatments today damage normal as well as malignant tissue, making such side effects as hair
loss and nausea all too familiar to cancer patients undergoing conventional therapy.
But SHALs, like a Trojan horse, can be designed to carry their means of destruction with them, in the
form of a radioactive isotope or potent anti-cancer drug. After seeking out and binding to cancer cells,
SHALs can unleash their weaponry locally, minimizing the risk to normal cells. This would be a particular
boon to patients with metastatic disease, in which a cancer has spread throughout the body.
Gerald and Sally DeNardo, co-directors of the Radiodiagnosis and Therapy Program at UC Davis, are testing
radionuclide-toting SHALs to attack non-Hodgkin's lymphoma cells in mice, an application that may be used
in human clinical trials within the next few years. If this is successful, doctors one day may be able
to deliver lethal radiation specifically to cancer cells, sparing normal tissue.
Nanotechnology, which encompasses minute biologics and machines on the scale of nanometers, has the potential
to transform every medical discipline as well as a host of industries. Governments and private companies
worldwide are jumping on the nano-bandwagon, investing around $8.6 billion in 2004.
"Nanotechnology is poised to enable radical new approaches in basic cancer research and clinical
cancer care," says Anna D. Barker, deputy director for strategic scientific initiatives with the
National Cancer Institute, which last summer earmarked $144.3 million for nanotechnology research over
the next five years.
Nanotechnology's diminutive size gives it such enormous potential in medicine: nanosize molecules can
cross membranes, enter cells and interact with other molecules within and among cells. "You need
to get to a certain scale to gain access," Balhorn says. "Nanotechnology gives scientists the
ability to actually mimic biologic processes."
How to make a SHAL
To design a SHAL, Balhorn and his team perform computer searches of databases that list all commercially
available organic molecules, including sugars, amino acids, dyes and detergents some 300,000 in
all to find the best match for a target site. He then combines the chosen fragments into a single
molecule and mixes this newly created particle with his target to see if they bind.
High affinity for the target is important, not just so the SHAL can do its job, but also so that it can
outperform other molecules in the body that may fit the same target. If necessary, Balhorn can tinker
with a SHAL to enhance its affinity for a particular target. For example, he has found that connecting
two of his "best-fit" molecules with a "linker" molecule improves its affinity up
to a million-fold.
The synthetic molecules he creates act just like antibodies in the immune system, Balhorn explains. But
unlike natural antibodies, SHALs are often too small to elicit an immune response and therefore
aren't destroyed by our body's natural defenses.
Along with his colleagues in the new field of nanotechnology, Balhorn has big dreams for these tiny tools:
He hopes SHALs will revolutionize how researchers and clinicians learn about, diagnose and treat cancer
and many other diseases of our time.