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.