Researchers report the engineering of a nanoscale drug delivery system, consisting of an inner nanoparticle core surrounded by a lighter outer envelope, thus named a “nanocell,” that enables the release of two drugs. The technology, they say, offers an effective way to deliver combination therapies for cancer.

“The work involves an understanding of cancer biology and bringing in the pharmacology and engineering design to take on, not only the mainstay of cancer treatment, which right now is chemotherapy, but also to bring in the newer, exciting strategy of targeting the tumor blood vessels that bring nutrients to the tumors,” says Ram Sasisekharan, PhD, professor of biological engineering, Massachusetts Institute of Technology, Cambridge, and senior author of the study, to be published in Nature. By bringing these two treatments together in a smarter package they believed they could achieve a more effective combination effect.

The group of researchers, led by Sasisekharan, tested the effectiveness of the nanocell technology in mice with melanoma and Lewis lung cancer by conjugating a chemotherapeutic agent (doxorubicin) to the inner nanoparticle with an anti-angiogenesis agent (combretastatin) trapped within the lipid envelope. “Each of these compartments act in concert,” says Sasisekharan.

“By designing the right size particles and given the profusion properties of the tumor microenvironment, there is a selective uptake of the nanoparticles, which get trapped in the tumor,” he says.

The nanocells, which are administered by injection into the blood, get trapped in the tumor microenvironment and act as a balloon within a balloon. The outer balloon bursts and releases the anti-angiogenesis drug that causes the vascular shutdown, cutting the supply lines to the tumor. Then, the specially formulated polymer that forms the inner balloon slowly releases high concentrations of the cytotoxic agent.

By cutting off the tumor cells first the toxicity of the cytotoxic agent is reduced, says Sasisekharan. They also used polymer and lipid systems that have been used in humans and are known to be safe, as well as off-the-shelf drugs.

“When you look at chronic or acute disease, often, in the tissue microenvironment, there are different compartments that are involved,” says Sasisekharan. “This approach could be extended beyond cancer. Cancer was obviously a good application because of the excitement around the newer strategy of targeting the vasculature system and the fact that we really need more effective therapy that not only shows an improved therapeutic index of the chemotherapeutic drug, but also reduces the toxicity.”

Of the mice receiving the dual-drug nanocell, 80% survived beyond 65 days, while mice treated with single therapies survived 30 days. Untreated animals died in 20 days. “It was remarkable to see the survival times, which are pretty significant in terms of the time lines in mice,” Sasisekharan says. “It gives us the hope that, if optimized in the right way, we may see similar effects in humans and I hope we do.”

By Elizabeth Tolchin