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.
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.
Hasan believes that's because the nanocells actually fuse with the tumor cells and deliver the Avastin inside the cell, instead of just to the outside. And though Hasan's lab has not done any toxicity studies, she hopes that the nanocells' preferential accumulation inside of tumors may decrease the drug's side effects, which can be quite dangerous. As many as 30 percent of patients receiving Avastin suffer cardiovascular side effects, including dangerously high blood pressure, stroke, and heart failure.
Shiladitya Sengupta, an assistant professor of medicine and health sciences and technology at Harvard Medical School, calls the results of Hasan's mouse experiments "dramatic." He says, "In the context of pancreatic cancer, [the results are] outstanding, because there's no therapy."
Sengupta did not participate in Hasan's research, but he originated the idea of drug delivery using nanocells. Technology Review recognized him for this idea with a 2005 TR35 award. He cofounded Cerulean Pharma to commercialize the nanocell platform and other nanopharmaceutical delivery methods. But one tricky aspect of the technology is that it must be individually optimized for every new combination of drugs, he notes.
Hasan's team has already developed a second nanocell designed to prevent pancreatic cancers from developing resistance to chemotherapy, a very common problem. Other researchers have identified two proteins, EGFR and MET, as particularly important in the development and growth of pancreatic cancer. In fact, in cancer cell lines in the lab, when biologists block EGFR, the cells increase their production of MET, and vice versa. So to better control the tumors, Hasan's team set out to target EGFR and MET simultaneously, while again hitting the tumor with light to increase the effectiveness of the treatment.
This second nanocell required a more sophisticated design. Rai started with a small molecule called PHA-66572, which inhibits the MET protein, and confined it in the same sort of solid polymer nanoparticle used in the first nanocell. He then surrounded those nanoparticles with cetuximab, an antibody that blocks EGFR. Finally, he incorporated Visudyne into a lipid sphere that he used to encapsulate these two layers.
Zheng says that tumors shrank dramatically in mice that had been implanted with pancreatic cancers and then given a single injection of the nanocells followed by light therapy. He is still measuring the effects on metastasis, but since the MET protein is active in most cancers that have metastasized (not just pancreatic cancer), the researchers are optimistic that the growth-factor nanocells will significantly decrease the number and size of metastases as well.
Zheng says that these results are particularly encouraging because of the apparent reduction in toxicity of the drugs. Pfizer developed PHA-66572 specifically to block MET in cancer cells, but it proved so toxic that the company abandoned the drug. In contrast, Zheng says that the animals that he gave the nanocell maintained normal activity levels and didn't lose weight.
Hasan hopes that both nanocells will be tested in pancreatic cancer patients within just a few years. Because Avastin and Visudyne are already FDA-approved, their two-part nanocell will likely be the first tested, probably in about two years, but perhaps as soon as a year from now, she says.
The NCI is already conducting toxicology tests of the Avastin-Visudyne nanocell as part of a new drug application to the FDA. The growth factor nanocell should enter the clinic "soon after," Hasan says. The key is finding the best MET inhibitor, and Hasan says that other researchers are already testing several promising candidates.
By Erika Jonietz