For most cancer patients, it’s not the original tumor that poses the greatest risk. It’s the metastases that invade the lung, liver, and other tissues. Now, researchers have come up with an approach that tricks these spinoff tumors into swallowing poison. So far the strategy has only been tested in mice, where it proved highly effective. But the results are promising enough that the researchers are planning to launch clinical trials in cancer patients within a year.
The new work is “very innovative stuff,” says Steven Libutti, a geneticist and cancer surgeon at the Albert Einstein College of Medicine in New York City, who was not involved in the study. The treatment, he explains, works in three steps to place a conventional chemotherapeutic agent near the nucleus (or nuclei) of a metastatic cancer cell where the drug molecules are most lethal. “It’s almost like a multistage rocket” that lifts astronauts off Earth, sends them to the moon, and returns them safely, he says.
At the heart of the new therapy is a chemotherapeutic agent called doxorubicin (dox). The drug has been a mainstay of cancer treatment for years, as it jams up DNA in the cell nucleus and prevents tumor cells from dividing. But when it’s injected into the bloodstream, the drug can also kill heart muscle cells and cause heart failure, which often forces oncologists to either dial back the dose or discontinue it altogether. Delivering dox only to tumor cells is therefore highly desirable, but it has been a major challenge.
Hoping to provide such cell specificity, researchers led by Mauro Ferrari, a nanomedicine expert, as well as president and CEO of the Houston Methodist Research Institute in Texas, have spent years developing porous silicon particles as drug carriers. The particles’ micrometer-scale size and disklike shape allows them travel unimpeded through normal blood vessels. But when they hit blood vessels around tumors, which are typically malformed and leaky, the particles fall out of the circulation and pool near the tumor. That was step one in delivering chemotherapeutic drugs to their target. But just filling such particles with dox doesn’t do much good, Ferrari says. Even if a small amount of the drug finds its way inside tumor cells, those cells often have membrane proteins that act as tiny pumps to push the drug back outside the cell before it can do any damage.
To get large amounts of dox inside the metastatic tumor cells and then past the protein pumps, Ferrari and colleagues linked numerous dox molecules to stringlike molecules called polymers. They then infused the dox-carrying polymers into their silicon microparticles and injected them into mice that had been implanted with human metastatic liver and lung tumors. As with the previous studies, the researchers found that the silicon particles congregated in and around tumor sites, and once there the particles slowly degraded over 2 to 4 weeks.
As they did so, the silicon particles released the dox-carrying polymer strands. In the watery environment around tumor cells, the strands coiled up into tiny balls, each just 20–80 nanometers across. That size, Ferrari says, is ideal, because it’s the same size as tiny vesicles that are commonly exchanged between neighboring cells as part of their normal chemical communication. In this case, the dox-polymer balls were readily taken up by tumor cells. Once there, a large fraction was carried internally away from the dox-exporting pumps at cell membrane and toward the nucleus. Ferrari says at this point his team isn’t sure exactly why the dox-laden balls are ferried toward the nucleus, though this is exactly what they wanted.
Not only is the region around the nucleus devoid of dox-removing pumps, but it typically has a more acidic environment than near the cell membrane. And Ferrari’s team used this to their advantage as well. They designed the chemical links between dox molecules and the polymer to dissolve under acidic conditions. This releases the dox at the site where its cell killing potency is highest.
Up to 50% of cancer-bearing mice given the treatment showed no signs of metastatic tumors 8 months later, the researchers report today in Nature Biotechnology. In humans, Ferrari says, that’s equivalent to being cancer-free for 24 years. “If this research bears out in humans and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years,” Ferrari says. “That’s essentially providing a cure in a patient population that is now being told there is none.”
The new treatment isn’t the first nanomedicine to show promise. According to a recent nanotechnology working group study published in The Lancet, more than 50 nanomedicine compounds are now in clinical trials. However, the new work is promising, Libutti says, because the silicon microparticles tend to target tumors in the liver and lung, common destinations of metastatic tumor cells.
The new work holds out hope for improving the effectiveness of other chemotherapy drugs as well, Libutti says. “There’s no reason to believe you couldn’t make a version of these particles with any chemotherapeutic agent.”