Yolonda Colson, MD, PhD, is testing a small solution to the
problem of lung cancer recurrence following surgery – small enough
to fit millions of times into a grain of sand.
Colson, a cardiothoracic surgeon in the Dana-Farber/Brigham and
Women's Cancer Center, is a pioneer in the study of nanoparticles –
specks of material billionths of a meter long – as delivery
vehicles for chemotherapy drugs. Though her work has centered on
laboratory tissues and animal models, its potential for leading to
new therapeutic approaches is, for now, wide open.
The allure of nanoparticles in cancer medicine is that they
offer a way of ferrying chemotherapy agents directly to cancer
cells and of releasing those agents steadily over time, Colson
says. Their minute size means there are few barriers to their
reaching and entering cancer cells to deliver their medicinal
payload. It also gives them the versatility to potentially be used
against a variety of tumor types.
"Because they can be engineered for specific tasks,
nanoparticles can control the delivery of therapy to diseased
cells," Colson says. "Although research is still in a relatively
early stage, we see a great deal of promise in it."
Colson's work addresses an inherent shortfall of lung cancer
surgery: the tendency of the cancer to reappear either at the site
of surgery or elsewhere, through metastasis (spreading), in the
body. Local recurrences arise if hidden cancer cells remain after
surgery, as when surgeons cut close to a cancer to avoid damaging
adjacent vital organs such as the heart. Metastasis can result if
cancer cells escape the lung prior to surgery.
Current efforts to prevent or delay local recurrences with
chemotherapy agents are not always successful. One problem is that
chemo drugs are often very strong, but only for a short period of
time. They go to work right away, killing all kinds of growing
cells, even "good" ones trying to heal after surgery. A better
technique than the all-at-once methods would still deliver chemo
directly to the cancer cells but at a slower rate.
Here, nanoparticles may be just what the doctor ordered. In
animal studies, Colson attached a polymer film – a synthetic mesh
that held chemotherapy drugs at the site where a lung tumor was
removed. The mesh released the drugs into the surrounding tissue in
low, steady amounts for more than 50 days. After 90 days, none of
the animals had developed a recurrence at the site of the suture.
By contrast, 80 percent of the animals that received a direct
application of chemotherapy, or had a drug-free polymer stitched
in, developed a recurrence in that time.
A second focus of Colson's research is metastatic disease. With
current treatments, approximately 60 percent of people with stage 1
lung cancer – in which tumors are apparently confined to the lungs
themselves – are alive five years later. For the less fortunate,
death often results from cancer cells that have slipped away from
the lung and traveled the bloodstream or lymph system to form
tumors elsewhere. For lung cancer specialists, the question is
whether tumor cells are already in circulation at the time of
surgery, unbeknownst to doctors, or whether the problem begins with
tumor cells left over from surgery. In either case, can drug-toting
nanoparticles hunt such cells down and kill them?
To find out, Colson and her colleagues took a different type of
polymer, mixed in chemotherapy agents, and made very small
drug-containing nanoparticles. These were then injected into the
skin of laboratory mammals. As hoped, the particles traveled to
lymph nodes in the animals' groins, the same route that tumor cells
would take. "It was clear that the drug accumulates in the same
place that tumor cells tend to accumulate," states Colson.
Colson's team ran experiments using two different types of
particles. The first are sensitive to the pH level – or degree of
acidity – in a tumor cell's interior. After making their way inside
a cancer cell, the change in pH prompts them to expand and release
their cargo of chemo, killing the cell. The second variety is
similar to more standard types of nanoparticles, which do not
expand but release drugs by a different mechanism.
To the researchers' surprise, laboratory tests showed that the
expanding type was a more effective cancer cell killer than those
that did not expand. The reasons for this aren't clear, but Colson
speculates that expansion keeps the nanoparticle and chemo inside
the cancer cell longer, so it can do its work.
To develop nanoparticles for her research, Colson has worked
closely with Mark Grinstaff, PhD, a polymer chemist at Boston
University. The particles being studied trap chemotherapy inside
them, forming a tight ball that doesn't let water in or drug out
until the proper conditions are reached.
"Much work remains to be done before this approach is ready for
clinical testing in patients," Colson remarks. "The ultimate goal
is to make nanoparticles attack and kill only cancer cells.
Although reaching that goal will be hard, it only takes one day in
clinic telling patients that they have lung cancer to remind me
that any amount of work to achieve a cure would definitely be worth
– Rob LevyRobert_Levy@dfci.harvard.edu
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