Nanotech News

August 1, 2005

Nanoscale “Cell Within A Cell” Delivers
Multiple Therapies that Kill Tumors

Imagine a cancer drug that can burrow into a tumor, seal the exits and detonate a lethal dose of anticancer toxins, all while leaving healthy cells unscathed. Investigators at the Massachusetts Institute of Technology have designed a multifunctional nanoparticle to do just that. The dual-chamber, double-acting, drug-packing "nanocell" proved effective and safe, with prolonged survival, against two distinct forms of cancers-melanoma and Lewis lung cancer-in mice. This work, conducted by a multidisciplinary team led by Ram Sasisekharan, Ph.D., of MIT, was published in the journal Nature.

Chemotherapy-loaded nanoparticles, left, form the core of the nanocell, right, as seen under the electron microscope. The outer lighter layer of the nanocell stores the drug that cuts blood supply after the nanocell has entered the tumor.

Image Courtesy of Sasisekharan Lab

"The fundamental challenges in cancer chemotherapy are its toxicity to healthy cells and drug resistance by cancer cells," Dr. Sasisekharan said. "So cancer researchers were excited about anti-angiogenesis," the theory that cutting off the blood supply can starve tumors to death. That strategy can backfire, however, because it also starves tumor cells of oxygen, prompting them to release a cell signaling molecule known as hypoxia-inducible factor-1a (HIF1a), which triggers metastasis and the development of resistance to further chemotherapy.

The next obvious solution would be combining chemotherapy and anti-angiogenesis – dropping the bombs while cutting the supply lines. But combination therapy confronted an inherent engineering problem. "You can't deliver chemotherapy to tumors if you have destroyed the vessels that take it there," Dr. Sasisekharan said. Also, the two drugs behave differently and are delivered on different schedules: anti-angiogenics over a prolonged period and chemotherapy in cycles.

"We designed the nanocell keeping these practical problems in mind," he said. Using two different widely studied biocompatible polymers, Dr. Sasisekharan and his colleagues created a balloon within a balloon, resembling an actual cell. The MIT team loaded the outer membrane of the nanocell, made of pegylated-phospholipid block-copolymer, with the anti-angiogenic drug combrestastatin. The inner balloon, composed of the polymer PLGA, was loaded with the chemotherapy agent doxorubicin.

Incorporating polyethylene glycol (pegylation) in the outer membrane creates a "stealth" surface chemistry that allows the nanocells to evade the immune system. The size of the nanocells, approximately 200 nanometers in diameter, allows tumor cells to take them up preferentially compared to other cells. Once the nanocell is inside the tumor, its outer membrane disintegrates, rapidly deploying the anti-angiogenic drug. The blood vessels feeding the tumor then collapse, trapping the loaded nanoparticle in the tumor, where it slowly releases the chemotherapy.

The team tested this model in mice. The double-loaded nanocell shrank the tumor, stopped angiogenesis and avoided systemic toxicity much better than other treatment and delivery variations.

But it is patient survival and quality of life that really inspire this research, Dr. Sasisekharan said. Eighty percent of the nanocell mice survived beyond 65 days, while mice treated with the best current therapy survived 30 days. Untreated animals died at 20.

The nanocell worked better against melanoma than lung cancer, indicating the need to tweak the design for different cancers. "This model enables us to rationally and systematically evaluate drug combinations and loading mechanisms," says Dr. Sasisekharan. "It's not going to stop here. We want to build on this concept."

This work appears in a paper titled, “Temporal targeting of tumor cells and neovasculature with a nanoscale delivery system.” The full-text paper is available free at the journal’s website.
View abstract.