Targeting disease: Nanoparticles could deliver chemotherapy drugs directly to tumors to increase the impact and reduce side effects. (© Nicolle Rager Fuller, Sayo-Art)
Magic Nano-Bullets
Submicroscopic techniques that could kill cancer or mend weak hearts will only be used if they target the right cells and leave others unharmed. After years of development, Robert Langer at the Massachusetts Institute of Technology and his colleagues will soon begin clinical trials of "magic bullets" that employ nanotechnology to deliver drugs only where they are needed. It's no surprise to find Langer guiding such a futuristic approach. "Langer is a living legend in the area of drug delivery," says Chad Mirkin, a nanomedicine researcher at Northwestern University. "He is to drug delivery what Ford was to automobiles!"
Nanotechnology works with construction blocks that are only nanometers—billionths of a meter—across. So far more than two dozen nanotechnology therapies have been approved for clinical use. These are mostly relatively simple improvements of existing drugs, Langer explains. For example, the potent anticancer compound paclitaxel, commonly known as Taxol, does not dissolve well in water, and toxic detergents were used to administer it in the bloodstream. The drug Abraxane incorporates paclitaxel in nanoparticles of the human protein albumin that render the drug soluble in water, while reducing unwanted side effects.
Instead of upgrading past drugs, Langer hopes to bring entirely new classes of therapies into the clinic with a Swiss Army knife's worth of options. He and his colleagues are designing biodegradable, organic-polymer nanoparticles that include therapeutic agents and molecules that bind to the desired targets. Moreover, the nanoparticles are formulated to evade the immune system. "The hope," Langer says, "is to have these ‘magic bullets' that can hone in on specific cells."
Simplification With Self-Assembly
Although the first targeted nanoparticle–drug delivery systems appeared as early as 1980, creating ones that work consistently has proven challenging. Each desired feature of a nanoparticle typically requires laborious sets of chemical reactions. Every step can introduce variability, and the delicate balance needed between all these features for a successful drug-delivery system can readily get lost. But Langer, along with colleague Omid Farokhzad at Harvard Medical School, developed a way for nanoparticle–drug delivery systems to self-assemble in a single step, eliminating much of the imprecision that could prevent nanoparticle consistency.
Others in the field respect the work of Langer and Farokhzad. "My group follows their work very closely. They are trendsetters in lots of different ways," says Joseph DeSimone at the University of North Carolina at Chapel Hill. "This team is playing a leadership role internationally in drug delivery."
Langer and Farokhzad have started two venture-backed companies to commercialize polymer-nanoparticle drug delivery. BIND Biosciences will begin clinical trials this year on the first polymer nanoparticle to enter tests that delivers a chemotherapy drug in a targeted way. As Farokhzad says, "In experiments, our targeted nanoparticles worked significantly better than traditional chemotherapy and non-targeted nanoparticles." BIND will also target cardiovascular disease. Langer and Farokhzad's other company, Selecta Biosciences, focuses on delivering specific disease-linked molecules to immune cells, serving as improved vaccines.
The advantage of using polymer nanoparticles in drug delivery is the enormous control that scientists have over the characteristics of the particles—the fruitful results of years of polymer research. Langer has been on the forefront of polymeric drug delivery for more than three decades, having invented the first polymer that allowed the controlled release of a drug in the body.
Instead of trying to predict which combination of polymer nanoparticles works best as a delivery agent, as other labs do, Langer and Farokhzad create libraries of hundreds of particles—each with its own array of distinct characteristics—and then rapidly screen them against a particular ailment to find the optimal agent. This approach has already revealed some surprises. For instance, researchers once thought that increasing the number of binding molecules created a better-targeted nanoparticle, but Langer and Farokhzad's technique showed that less sometimes works better.
Extending The Nano-Arsenal
A number of other nanotechnology approaches toward drug delivery exist. Hongjie Dai at Stanford University and his colleagues have shown that carbon nanotubes can bring proteins and DNA into cells, which could potentially deliver drugs or therapeutic genes. In addition, Donald Tomalia, scientific director of the National Dendrimer and Nanotechnology Center, explores spherical branching molecules named dendrimers, which resemble bushes in structure. Scientists can precisely tailor what each branch tip holds, enabling dendrimers to combine a number of different therapies and delivery tools.
"Carbon nanotubes and dendrimers are both extremely promising for drug delivery," Farokhzad notes. "But carbon nanotubes are really in their infancy clinically speaking. It’s going to take a number of years before the safety of these materials is understood. And dendrimers are exciting, but then there's the question of how amenable they are to scaling up in production. Making polymer particles is a relatively easy process to scale up, and polymer-particle drugs have already been approved by the FDA for 15 or so years now."
One feature that is simultaneously attractive and alarming about nanotechnology is that objects at the nanometer scale can take on radically different properties not seen in their bulk counterparts. For instance, while gold is normally chemically inert, which keeps gold rings lustrous, gold nanoparticles can prove highly reactive. Any unknowns about potential therapies could pose nasty risks, so when developing nanoparticles for the clinic, Langer and Farokhzad stick to polymers that are well-understood and drugs that are already approved.
In their research, however, Langer and Farokhzad are known to push the envelope. In 2008, for example, they developed a nanoparticle that combined immune-system stealth, disease targeting and drug release. It could also detect the location of tumor cells and indicate when the nanoparticles delivered the drug to their targets. "That technology is very futuristic, and whether so many bells and whistles are needed with these nanoparticles is a good question," Farokhzad says. "But I'd say we have to be innovating today if we want the luxury of applying that technology tomorrow. We might be paving the road for 30, 40, 50 years from now. The impact of nanotechnology on medicine is just beginning, and I think it will be huge in our lifetime."
