Research is showing that nanotechnology may be the next “big thing” for drug delivery and diagnostics.
“I just want to say one word to you, just one word. Are you listening? Plastics.”
–Mr. McGuire in “The Graduate” (1967)
If the classic Dustin Hoffman film “The Graduate” were made today, a modern Mr. McGuire would surely give the protagonist a different one-word prescription for success: nanotechnology. Like plastics in the 1960s, nanotechnology is filled with both genuine potential and non-skeptical hype. And there is little doubt that, for better or worse, it will soon infiltrate nearly every aspect of our lives.
Numerous products, ranging from car wax to shampoo, already claim to contain nanotechnology, but most experts seem to agree that the field’s biggest breakthroughs are still a few years off. Indeed, techniques now being developed in nanotechnology laboratories could revolutionize drug delivery and development.
Having honed their ability to manipulate individual molecules with extraordinary precision, nanotechnologists in several labs are now working to produce a new generation of drug delivery systems. For a drug industry grappling with increasingly complex treatment regimens and thorny delivery problems, those systems can’t come too soon.
“There’s a huge unmet need out there of having an effective carrier that’s able to deliver a cargo that’s nontoxic and could be amenable for chronic treatments,” says Joseph DeSimone, PhD, professor of chemistry at the University of North Carolina at Chapel Hill, N.C. Basic researchers have been trying to address that need for years, of course, but with the latest batch of nanotechnologies they may finally have the tools to do it.
Gold for what ails you
One of the most advanced nanotechnology-based therapies that is currently in clinical trials relies on gold nanospheres to target diseased tissue, especially tumors. The spheres, developed by Naomi Halas, PhD, a professor of bioengineering at Rice University in Houston, Texas, consist of silica cores wrapped in gold atoms. Each sphere is about 100-nm in diameter. Decorating the outsides of the spheres with antibodies against a tumor antigen makes the particles stick to tumor cells.
Once the nanoparticles accumulate in the tumor, the researchers can attack the cancer cells in a variety of ways. Properly-tuned nanoshells can resonate and heat up in response to tissue-penetrating near-infrared light, cooking adjacent tumor cells to death. The researchers are also modifying the system to deliver drugs. “We do that by combining the nanoparticle itself with other materials that are thermally responsive … and so then the drug is released above a certain temperature,” says Halas.
Though cancer is the first indication the team has pursued, Halas is quick to point out that the system could also help treat a wide range of other conditions. “It could be appropriate for cases of injury and inflammation, it could be appropriate for … transplant rejection,” she says.
Besides routing a drug to a specific part of the body, nanospheres might also allow drug developers to fine-tune a compound’s pharmacokinetics. “What’s becoming clear is that if you tether that drug molecule to a nanoparticle or several of those molecules to a nanoparticle, then you can certainly influence the way in which those particles leave the body,” says Halas. For example, adding a properly designed nanoparticle could target a compound for elimination through the liver instead of the kidneys, if it proves toxic to the latter.
The technology could also be useful in diagnostics, where the dosing of imaging dyes is often limited by the compounds’ toxicities in particular organs. “By binding this to a nanoparticle you can actually … alter its pharmacokinetic pathway in a good way, so it will no longer have any toxicity issues,” says Halas.
PEG, squared
Gold nanoparticles aren’t the only way to change a drug’s pharmacokinetics, of
course. For years, drug developers have relied on simpler tricks, such as adding a polyethylene glycol (PEG) moiety to improve compounds’ bioavailability. While that strategy certainly works for some drugs, it’s not very flexible.
“With PEG, it’s been well demonstrated … that you can change properties of molecules, but you are hampered by the fact that it’s a bit like [Ford’s original] Model T technology, you can have anything you like as long as it’s black,” says John Tsanaktsidis, PhD, theme leader in nanomaterials for medical delivery at the Australian Commonwealth Scientific and Research Organization (CSIRO) in Clayton, Australia. Designing and synthesizing new polymers and getting them onto drugs are difficult, so chemists haven’t been able to move beyond PEG.
“When you’re developing a small molecule, for example, you play around with it, you make variants, you change this, you change that, and you effectively explore the structure-function relationship of the molecule as it interacts with its receptors,” says Tsanaktsidis. Using a new technique that combines elements of nanotechnology and traditional synthetic chemistry, he and his colleagues now hope to bring similar capabilities to the polymer lab.
By growing polymers from a surface rather than preparing them in solution, the CSIRO team can produce a customized structure and attach it to a drug easily. “Whether that polymer’s going to be three units long or 50,000 units long, whether it’s globular in shape or … linear, all those questions we need to address, but [now] we can start probing that in a very systematic way,” says Tsanaktsidis.
Currently, the researchers are working on proof-of-concept experiments to improve the bioavailability of existing, well-characterized drugs. “That said, if somebody wants to come and play with us from this early stage with one of their molecules, we’d be happy to work with them as well,” says Tsanaktsidis.
Back to the grind
Other nanotechnologists are also looking to improve drug bioavailability. At Elan Drug Technologies in Dublin, Ireland, for example, researchers have perfected a method for grinding compounds into extremely fine, nanoscale powders. That may not sound very impressive, but the results speak for themselves; Elan’s NanoCrystal technology can improve the bioavailability of drugs as much as six-fold, in at least one case turning a “non-druggable” compound into a marketable product.
“Any compound that is poorly water-soluble is suitable for application of the NanoCrystal technology,” says Gary Liversidge, PhD, senior director of Elan. “It is estimated that up to 40% of all drugs in development have poor water solubility challenges,” he adds.
Though the idea of grinding a compound to make it more soluble is ancient, several inconvenient physical phenomena
tend to keep ground-up particles from reaching the nanoscale. “One of the main challenges with producing such small nanoparticles is making a product with acceptably low levels of contamination from the attrition process,” says Liversidge. The researchers also had to stabilize the minuscule particles so they wouldn’t re-aggregate and grow back into larger crystals. A combination of proprietary polymeric media, stabilizer compounds, and other refinements finally got the procedure working.
By 2001, Elan’s researchers had finally worked the kinks out of the whole process, and since then the company has been capitalizing on its position as one of the first nanotechnology drug delivery companies to reach the market. NanoCrystals now deliver drugs such as Merck’s Emend (aprepitant) for chemotherapy-induced nausea, and an injected time-release version of Janssen’s Invega (paliperidone palmitate) for schizophrenia.
The shape of things to come
Many of the nanoparticles that are most promising for drug delivery, such as liposomes and nanospheres, are prepared by “bottom-up” synthesis, adding building blocks until the structure is done. That works well for small batches, but it can complicate large-scale manufacturing.
To get around that problem, DeSimone and his colleagues in North Carolina have developed a new “top-down” approach to nanoparticle synthesis. The technique, called particle replication in non-wetting templates (PRINT), borrows technology from the semiconductor industry to reel off large sheets of nanoparticle molds, which the researchers can then use to cast particles with uniform sizes and chemistries.
“We can control the size and shape, and so we’re making a wide range of filamentous or wormlike particles,” says DeSimone, adding that “there [are] some really important things in the literature on using size and shape to control where things go in vivo.” In particular, the researchers are trying to develop nanoparticles that copy successful biological structures. “Red blood cells are deformable, they can undergo one hundred percent strain, double in length, pop through the pores of the sinusoids in the spleen … and recirculate, so there’s this whole rich area of mechanobiology in understanding that, and we can mimic that,” says DeSimone.
Mass-producing consistent nanoparticles could also be a novel way to make vaccines, without the complications and potential contaminants that accompany current cell-based manufacturing methods. “We can conjugate an immunostimulatory molecule on the surface of a PRINT particle and deliver that, perhaps with an adjuvant, so there’s a whole host of opportunities … for design of vaccines,” says DeSimone.
About the Author
Originally trained as a microbiologist, Alan Dove has been writing about science and its interfaces with industry and goverment for more than a decade.
This article was published in Drug Discovery & Development magazine: Vol. 11, No. 11, November, 2008, pp. 22-24.
Filed Under: Drug Discovery