In a small manufacturing space on a Cambridge, MA, street dotted with biotech companies, Greg Troiano tinkers with a series of gleaming metal vats interweaved with plastic tubes. The vats are designed to violently shake a mix of chemicals into precise nanostructures, and Troiano’s task, as head of process development at start-up BIND Biosciences, is to make kilograms of the stuff–a novel drug-infused nanoparticle. The company hopes the new drug-delivery system will diminish the side effects of chemotherapy while increasing its effectiveness in killing cancer.
Scientists at BIND have shown that their nanoparticles–which are not only infused with drugs but also enrobed in cancer-targeting proteins–can better stop the growth of prostate, breast and lung tumors in rodents. BIND has made particles that can remain in the bloodstream for more than a day, increasing the likelihood that the drug will reach its target tissue. It is also refining a method for making large volumes of its nanoparticle-based delivery system in preparation for clinical trials of its technology in cancer patients next year.
The company’s approach is based on self-assembling polymers developed in the lab of Robert Langer, a professor of chemical engineering at MIT and a pioneer in biomaterials research. Langer founded BIND in 2006 with Omid Farokhzad, a scientist and physician at Harvard Medical School and a former postdoctoral researcher in Langer’s lab.
“The idea of using nanoparticles is to lower the dose while maintaining efficacy and reducing side effects,” says Piotr Grodzinski, director of the Nanotechnology for Cancer Programs at the National Cancer Institute, in Bethesda, MD. Grodzinski said in some cases the nanoparticles could be used to increase the dose while reducing toxicity. This is especially important for chemotherapeutics, which often must be administered in high doses that result in severe side effects–so severe that some patients choose to forgo the treatment.
A few existing drugs and a number in development use lipid-based nanoparticles and other technologies to extend the lifespan of the drug in the bloodstream, allowing more of the compound to reach the target tissue through the blood vessels. But none have yet both targeted the drug to the desired cells and boosted its circulation time.
The core of BIND’s nanoparticle is made up of biodegradable polymers PLA (polylactic acid) and PLGA (copolylactic acid/glycolic acid), which hold the desired drug in a molecular mesh, allowing it to slowly diffuse. The outer layer is made of polyethylene glycol, a molecule with water-like properties that lets the nanoparticle evade detection by proteins and the white blood cells that eat pathogens in the blood. That stealth coating is also dotted with specially designed peptides that bind to the cell of interest, delivering the particle’s payload.
When the three components are mixed together under carefully controlled chemical conditions, the structured nanoparticles form spontaneously. “Because the self assembly doesn’t require multiple complicated chemical steps, the particles are very easy to manufacture,” says Farokhzad. “And we can make them on a kilogram scale, which no one else has done.” In most other targeted nanotechnologies, the core particle is made first and later coated with the targeting molecule, a more complex process that can be difficult to precisely repeat.
Mimicking the screening process that drug developers use to find the optimal candidate molecule, researchers at BIND generate hundreds of versions of nanoparticles for each drug and then screen each to find those that can survive in the bloodstream the longest and have the best tissue-targeting capabilities. By slightly varying the concentrations of each of the three components, the researchers can generate particles that have a different size, surface charge, and concentration of targeting molecules on its surface.
“It’s a fine balance between stealthiness and targeting,” says Jeff Hrkach, vice president of pharmaceutical sciences at BIND. “With too much of the targeting ligand, the particle will get cleared from the bloodstream.” While scientists have traditionally tried to pack as much of this marker as possible onto the nanoparticle in order to enhance its targeting prowess, Langer and Farokhzad found that fewer of these molecules actually work better.
So far scientists at BIND have tested the technology with 15 different drugs for cancer, cardiovascular disease and inflammatory diseases, but are focusing first on chemotherapeutics. Testing the drug-laden particles in mice engineered to have human tumor cells, researchers showed that animals treated with the nanoparticles had a much higher concentration of drug in the tumor–up to 20 times higher–12 hours after delivery than did animals given the naked drug. The nanotech version of the drug was also able to stop the growth of breast, prostate and lung tumors more effectively than either the drug alone or the drug delivered via nanoparticles lacking the targeting molecules.
BIND scientists have also enhanced circulation time from three to six hours to 24 to 72 hours, according to results presented last month at a conference at the National Cancer Institute. “They showed some really impressive circulation times,” says Joseph DeSimone, a chemist at the University of North Carolina, Chapel Hill, who is not involved with the company. “It looked much longer than other things I’ve seen in the literature.”
For its planned tests of the technology next year on human subjects, the company has not yet specified the type of cancer or the chemotherapy drug to be used. It is, however, scaling up the manufacturing process in order to make enough of the particles for clinical tests.
In addition to existing drugs, BIND is working with undisclosed pharmaceutical companies to determine whether candidate drugs, including those that might have been shelved because of problematic side effects or other issues, might be enhanced or revived with targeted nanoparticle delivery.