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 therapy is based on a drug called called doxorubicin, or dox. This is a common agent in chemotherapy because it binds to DNA and keeps tumor cells from dividing. However, it is just as toxic to certain regular cells as it is to cancer cells, especially cells in the heart. So patients often have to discontinue treatment because of heart issues. So it would be nice to deliver it directly to cancer cells:
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.Amazing, the things we can do. On the other hand, we're still not very good at fighting most dangerous cancers, so we'll have to see if these nano-particle approaches can be made to work.
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.”