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Targeting Therapeutics to Cancer Cells Enhances Existing Chemotherapy While Cutting Side-Effects

It isn't hard to kill cells; "bleach works just fine," as I was told by a researcher some years ago. The challenge lies in killing only a specific set of cells in a living organism, and without greatly harming the organism in the process. Obviously something more discriminating than bleach is called for. The mainstay of the last generation of cancer therapies, chemotherapy, is a fine balance between harming cancer cells as much as possible while harming the patient as little as possible. It isn't a pleasant experience, and it does have significant and lasting negative impact. The best that can be said of it is that it is much better than the alternative. The promise of new technologies allowing delivery of therapeutics to individual cells based on their specific differences in surface or internal chemistry is that existing chemotherapy drugs can be used with minimal doses and near-absent side effects, and yet still be more efficient when it comes to removing cancerous cells. This is one example of many targeted delivery mechanisms under development or in trials:

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. Delivering dox only to tumor cells is therefore highly desirable, but it has been a major challenge. Thus researchers have spent years developing porous silicon particles as drug carriers. The particles' micrometer-scale size and disk-like 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. 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, researchers 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. 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 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.

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. The researchers 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 results are promising enough that the researchers are planning to launch clinical trials in cancer patients within a year. The new work holds out hope for improving the effectiveness of other chemotherapy drugs as well. "There's no reason to believe you couldn't make a version of these particles with any chemotherapeutic agent."

Link: http://www.sciencemag.org/news/2016/03/nano-balls-filled-poison-wipe-out-metastatic-cancer-mice

Comments

I have read so many articles about how nanoparticles will selectively kill cancer cells with little to no side effects for 5+ years. You would think it would be a matter of practice by now.

Well at least they are getting the immunity system to fight cancer if not nanoparticles. Still, it would be good have more tools in the toolbox for better treatment.

Posted by: Robert Church at March 17th, 2016 5:28 PM

Patience dude, it took decades of work to get chimeric antigen receptors working properly.

Posted by: Jim at March 17th, 2016 10:25 PM

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