Big Hope for Tiny Particles

Nanotechnology-based drug delivery offers new treatment options for deadly pancreatic cancers.

Nanoparticles that deliver two or more drugs simultaneously can significantly shrink pancreatic cancer tumors and also reduce its spread, say researchers at Massachusetts General Hospital. Tayyaba Hasan, who is also a professor of dermatology at Harvard Medical School, led the development and testing of two "nanocells." These nanocells combine light-based therapy with molecules that inhibit the growth of cancer cells or of the blood vessels that feed them.

Though the particles have only been studied in mice so far, the cancer-research community is excited. Pancreatic cancer remains one of the deadliest and hardest cancers to treat; mortality rates have changed very little in the last 30 years. After diagnosis, patients tend to live only six months, and less than 5 percent survive for five years. "In terms of a patient population, there is very little we can do for them once we find the cancer," says Craig Thompson, director of the Abramson Cancer Center at the University of Pennsylvania.

Hasan and two research fellows in her lab, Prakash Rai and Lei Z. Zheng, presented their initial results on November 17 at the International Conference on Molecular Targets and Cancer Therapeutics, held jointly by the American Association for Cancer Research, the U.S. National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer.

The team's first type of nanocell is designed to effectively starve tumors by cutting off their blood supply. They trapped a photosensitive drug called verteporfin, which creates toxic oxygen radicals when exposed to specific wavelengths of light, inside solid polymer nanoparticles. Those nanoparticles were then encapsulated in lipid particles along with bevacizumab, an antibody that specifically inhibits the growth of new blood vessels by blocking a protein called VEGF. Both verteporfin and bevacizumab are already approved by the U.S. Food and Drug Administration. Bevacizumab is approved for the treatment of advanced cancers of the colon, breast, lung, and kidney; it's marketed by Genentech as Avastin. Verteporfin is used to eliminate abnormal blood vessels in wet-form macular degeneration. It's sold as Visudyne by Novartis.

In a previous small-scale clinical trial, verteporfin alone increased the median survival of pancreatic cancer patients from six months to nine months. Adding Avastin, however, did not increase survival time--possibly because the Avastin killed off the tumor's blood vessels, making it difficult to get enough of the photosensitive drug to the cancer.

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In contrast, when the nanocells are injected intravenously, they deliver both drugs directly to the inside of cancer cells. Blood vessels in normal tissue are impermeable to the nanoparticles, but blood vessels in tumors are "leakier," with much larger pores that allow the nanoparticles to pass through. As a result, the nanoparticles accumulate inside tumors and deliver more of their payload to the cancer cells than to healthy cells. The nanocells provide a higher effective dose of drug to the tumors as well as fewer side effects because the researchers used a lower dose of both drugs than usual.

The team implanted human pancreatic cancer cells in mice and allowed tumors to grow. They then injected the mice with a single dose of the nanocells and exposed the tumor to long-wavelength light. Mice given this single treatment showed a greater reduction in their tumor size than mice treated with either drug alone. The mice treated with the nanocells also had at least two times fewer metastases to the liver, lungs, and lymph nodes. "Injecting these things as separate entities is not as effective as combining them into one construct," says Hasan.