February 26, 2009
Tiny particles offer big promise for lung cancer treatment

Nanoparticles carry chemotherapy drugs (shown as black dots) into cancer cells. Once inside, the particles change shape, releasing the drug. Illustration courtesy of Brigham and Women's Hospital 

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.

In circulation

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 it."

– Rob Levy
Robert_Levy@dfci.harvard.edu