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Programmable Nanoparticles Improve Chemotherapy's Aim
4 April 2012 4:39 pm
Chemotherapy drugs are like a shotgun. Even though doctors are just aiming for tumors, the compounds hit a variety of other places in the body, leading to side effects like bone marrow damage and hair loss. To improve their aim, researchers have tried to package these drugs inside tiny hollow nano-sized containers that can be directed toward tumors and bypass healthy tissues. But the size, shape, and makeup of these "nanoparticles" can drastically affect where and when they are taken up. Now, scientists have surveyed the landscape of some 100 different nanoparticle formulations and shown that when a conventional chemotherapeutic drug is packaged inside the best of these nanoparticles, it proves considerably more effective at fighting prostate cancer in animals than the drug alone.
The new results aren't the first to show the promise of nanoparticle therapeutics against cancer. Nearly a dozen of these tiny drug carriers are already in clinical trials. But researchers are still struggling to sort out the size and makeup of nanoparticles that work best for ferrying drugs to tumors. So for their current study, a team of 30 researchers led by chemical engineer Robert Langer at the Massachusetts Institute of Technology in Cambridge, physician-scientist Omid Farokhzad of Harvard Medical School, and biochemical engineer Stephen Zale of BIND Biosciences in Cambridge, Massachusetts, decided to take a more systematic approach.
Rather than looking at all types of biomaterials from which to make their particles, the researchers started with six different materials already approved for use by the U.S. Food and Drug Administration, as well as an already-approved anticancer cargo compound called docetaxel. They then varied 10 different factors, including the size of the particles in which they trapped docetaxel, the density of chemical groups used to shroud the particles from the immune system, additional surface compounds used to target the particles to tumor cells of interest, the amount of docetaxel they carried, and how fast the particles decomposed and released their cargo.
After a preliminary evaluation of more than 100 different nanoparticle drug formulations, Langer and his colleagues settled on a design containing 100-nanometer particles made from a combination of a biodegradable polymer known as PLA and a coating of PEG, another polymer that readily binds water molecules and helps hide the particles from the immune system. Some of the PEG chains were also capped with copies of a small molecule called ACUPA that binds to receptor molecules overexpressed on the surface of prostate cancer cells.
Tests on mice, rats, and monkeys showed that delivering docetaxel in nanoparticles produced plasma concentrations of the drug over a 24-hour period 100 times as high as standard docetaxel injections did; 10 times as much of the drug accumulated in tumors, as well. And in an early clinical safety trial on 17 people, the researchers found drug accumulation in tumors and clinical effects at doses as low as 20% of the normally prescribed docetaxel dose, as they report online today in Science Translational Medicine. Additional clinical trials are now testing increased doses, and no new toxicities have been observed to date.
"It's an important result, and a terrific direction to go in," says Joseph DeSimone, a chemist and nanoparticle drug expert at the University of North Carolina, Chapel Hill. The study shows that delivering drugs inside nanoparticles has the potential to improve the effectiveness of many conventional cancer drugs and other therapeutics that are limited by their side effects, he says: "When you change where drugs deposit, you fundamentally change the outcome."