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Dendrimers--treelike macromolecules with branching tendrils that reach out from a central core--have a way of grabbing scientists' imaginations. With dendrimers and dendritic polymers now playing key roles in new technologies and the first dendrimer-based pharmaceutical poised to enter the market as early as 2008, dendrimer scientists are hoping to snare profits as well.
Dendrimer research has been slowly but steadily gaining ground since the late 1970s, when scientists like Fritz Vögtle, at the University of Bonn, in Germany, and Donald A. Tomalia, then working for Dow Chemical in Midland, Mich., started to build the first of these branching molecules. A keyword search for "dendrimers" and "dendritic polymers" shows that the number of dendrimer-related papers published has grown from a handful in the early 1990s to nearly 1,000 papers in 2004 alone.
Researchers have made all manner of dendrimers: graphitelike dendrimers, light-harvesting dendrimers, dendrimers with cross-linked surfaces, dendrimers that self-destruct. Scientists have used the hollow cavities deep within the branching structures to hold metal nanoparticles, drugs, and imaging agents. Dendrimer researchers seem limited only by their creativity and, of course, the relatively high cost of making the dendrimers.
The macromolecules are constructed around a simple core unit. Each successive reaction introduces a new "generation" of branching. But as the molecules grow, the cramped conditions at the dendrimer's periphery lead to longer reaction times and more complicated mixtures of products from which the desired dendrimer has to be fished out. This means that dendrimers don't necessarily come cheap. Three hundred milligrams of a seventh-generation polyamidoamine, or PAMAM, dendrimer costs about $600.
NOT EVERYONE agrees that the cost of dendrimers is too high, however. "There are two myths about dendrimers," according to Sonke Svenson, a senior scientist at Dendritic NanoTechnologies in Mount Pleasant, Mich. "The first myth is that dendrimers in general are too expensive for commercialization, and the second is that the technology has been around for 20 years with no applications."
Svenson had these myths in mind when hammering out the scientific program of last month's Fourth International Dendrimer Symposium (IDS-4), held at Central Michigan University in Mt. Pleasant, with the meeting's other organizers--Tomalia, currently the president and chief technical officer at Dendritic NanoTechnologies; and professors Jean M. J. Fréchet of the University of California, Berkeley, and J. Fraser Stoddart of the University of California, Los Angeles.
"I decided that it is important to show that you can make money with dendrimers," Svenson told C&EN. As a result, the symposium's lineup featured a session on the commercial applications of dendrimers.
One myth-busting commercial application that the entire dendrimer community has been keeping an eye on comes from Starpharma, a firm based in Melbourne, Australia. Dendrimers' ability to ferry active compounds has gotten some attention from pharmaceutical companies for possible drug delivery applications, but it's the dendrimer itself that's the active ingredient in Starphama's new pharmaceutical.
The product, a topical vaginal microbicide called VivaGel, prevents infection by HIV and other sexually transmitted diseases during intercourse. The microbicide is the first and currently the only dendrimer-based pharmaceutical to be allowed to proceed into clinical trials by the Food & Drug Administration. VivaGel completed a Phase I human clinical trial last year, and Starpharma expects the clinical trials to expand this year, according to the company's chief executive officer, John Raff. Starpharma hopes to bring VivaGel to market by 2008.
In terms of debunking the myth that dendrimers have found no applications, it's hard to find a higher profile goal than HIV prevention. People like Magic Johnson have shown that it's possible to live long and healthy lives with today's HIV and AIDS treatments. But "that's in part because he's been able to afford the best medical care and the earliest intervention," said Tom McCarthy, Starpharma's development manager.
McCarthy noted that UNAIDS, the Joint United Nations Program on HIV/AIDS, estimates that 40 million people are infected with HIV worldwide. Last year, 4.9 million new infections were reported, and approximately half of those were in women. To help turn back the tide, scientists have been seeking HIV prevention agents. Microbicides offer one promising preventative measure, especially when it comes to treating the AIDS epidemic in developing nations.
VivaGel's HIV-fighting mechanism takes advantage of dendrimers' polyvalent properties. Depending upon which functional groups are attached to the tips of a dendrimer's branches, these nanostructures can behave like molecular Velcro. Simultaneously, these functional groups can participate in multiple interactions with receptors on biological structures like cell membranes and viruses.
According to Raff, this polyvalent binding mimics protein-protein and protein-membrane interactions and can lead to "significantly enhanced activity compared with traditional small 'single-binding' molecules."
The active ingredient in VivaGel is a fourth-generation polylysine dendrimer called SPL7013. Thirty-two naphthalene disulfonate moieties, attached via amide linkages, decorate the molecule's surface. This polyanionic structure prevents HIV infections by binding to the gp120 glycoprotein receptors on the virus's surface. The interaction in turn stops HIV from attaching to receptors on T cells in the body. McCarthy pointed out that this provides a protective effect against HIV that he and his colleagues tested in a demanding animal model of HIV infection (AIDS Res. Hum. Retroviruses 2005, 21, 207).
Starpharma plans to market VivaGel as an HIV prophylactic for women, initially on its own as a water-based gel and potentially as a coating on condoms. In preliminary studies, VivaGel has prevented herpes and chlamydia infections. In addition, Raff said that Starpharma has done some primate studies that demonstrated VivaGel can prevent rectal transmission of HIV.
DEBUNKING THE dendrimer expense myth, McCarthy noted that the projected cost of manufacturing 1 kg of SPL7013 comes to about $1,500. That cost, McCarthy added, translates to roughly 15 cents per dose.
Starpharma isn't alone in trying to take advantage of dendrimers' polyvalency to develop new therapies. Sunil Shaunak, a professor of infectious diseases at Imperial College London, and coworkers reported that they can prevent scar tissue formation using dendrimers with aminosaccharides and sulfated aminosaccharides covalently bound to the tips of some of a PAMAM dendrimer's branches (Nat. Biotechnol. 2004, 22, 977). They think the therapy will be particularly important in eye surgery, where even a small scar can result in blindness.
"The concept that we're pursuing is that whenever you get injured, two things happen," Shaunak explained. "One thing that happens is that you have to get new blood vessel formation, and the other thing that happens is that you get an inflammatory reaction." Whether the injury is a scraped knee or a surgeon's incision, these two biological events can cause scarring.
Most therapies are aimed at one of these two pathways, Shaunak continued, but with one path shut down, nature compensates by putting more energy into the alternate pathway, and scarring still occurs. "It reflects the remarkable redundancy that exists in most biological organs," he added. Shaunak's team decided to target both new blood vessel formation and inflammation at the same time.
Glucosamine fights inflammation, and glucosamine 6-sulfate has antiangiogenic properties. So Shaunak's group synthesized a PAMAM dendrimer that has both moieties attached to some of its branches.
In preliminary animal studies, the bifunctional dendrimer increased the long-term success rate of glaucoma surgery from 30% to 80%. Shaunak said that he hopes to begin clinical trials next year.
Before he stumbled upon dendrimers, Shaunak had spent 10 years trying to develop therapies based on linear polymers. While he was enthusiastic about the polyvalency effects they offered, he had grown frustrated with linear polymers' toxicity.
While attending a Gordon Research Conference in California in 1998, Shaunak shared this frustration with a fellow conference attendee over a couple of beers. "Well, what about using a dendrimer?" asked the stranger.
Shaunak remembered that his reply was something along the lines of, "How do you spell that?"
The stranger turned out to be Tomalia, and the two spent the next few hours discussing how dendrimers might be a good avenue for Shaunak to pursue.
"I had no idea who Donald was at the time," Shaunak admitted. But after their conversation, he returned to London energized and ready to give dendrimers a try. Tomalia's suggestion had been right on the mark. At therapeutic doses, the dendrimers didn't have the toxicity that had derailed his work with linear polymers.
Pharmaceutical makers aren't the only biomedical firms trying to capitalize on dendrimers' unique architecture. The molecules have also been gaining a reputation as useful tools for diagnostic applications. Dade Behring, a clinical diagnostics company headquartered in Deerfield, Ill., has been using dendrimers in its diagnostic technology since 1998. The molecules are a key component in the company's Stratus CS instrument for cardiac analysis.
Not everyone who arrives at the emergency room complaining of chest pains is having a heart attack. Doctors need to decide whether to treat that patient for a heart attack or indigestion. Pratap Singh, a scientist with Dade Behring, explained that the time it takes for the doctor to make that decision and begin treatment can have a huge effect on whether or not the patient's heart muscle suffers any permanent damage.
"An instrument like ours can help diagnose a heart attack in as little as 15 minutes," Singh said. The analyzer detects certain protein biomarkers that are released in the bloodstream as a result of heart muscle damage, he explained. The machine is small enough to fit on a standard hospital cart and features automated sample processing.
The technology uses antibodies immobilized on a specimen tester made of glass fiber paper as part of the biomarker detection system, according to Singh. And it's the dendrimers that anchor these antibodies to the glass. The fifth-generation PAMAM dendrimers that the Stratus CS employs are positively charged. Each antibody is covalently linked to the dendrimer, which, Singh explained, is immobilized on the negatively charged glass through electrostatics.
"It binds like glue," Singh said, adding that the antibodies are always oriented properly, too, thanks to the dendrimers' defined, regular, charged surfaces. Because no antibody is wasted, only microgram quantities of the pricey biological molecules are needed in each specimen tester.
"Dendrimer technology is highly reproducible, and that means more efficient, cost-effective manufacturing," Singh told C&EN. He said the Dade Behring scientists originally tried to anchor the antibodies directly to glass, but it was difficult to control the antibodies' orientation. Consequently, a lot of the material wouldn't bind the biomarkers and there was a lot of variation in the analyses. Singh said, "Once we moved to dendrimers, everything worked."
Magnetic resonance imaging is another diagnostic area where a number of scientists think dendrimers could improve upon existing technology. "Dendrimers are taking MRI contrast agents to a new level," Tomalia proclaimed.
It's an application with which Tomalia has a very personal connection. Twenty years ago, his wife, Jan, lost hearing in her right ear. At that time, contrast agents weren't used, and an MRI scan revealed nothing.
The Tomalias suspected the worst--that it was a malignant brain tumor. They spent years worrying that more severe complications would develop. It wasn't until years later--when an MRI scan was performed using a contrast agent--that they learned her hearing loss was caused by a benign acoustical neuroma.
THERE'S EVIDENCE that dendrimer-based contrast agents would be even better at detecting tumors than the small-molecule contrast agents, like Magnevist, that are currently in use.
Small-molecule MRI contrast agents feature a metal ion, most often gadolinium. According to Tomalia, because dendrimers can chelate or encapsulate many gadolinium ions in a relatively small area, they can give sharper, more detailed images than the small-molecule contrast agents.
Also, dendrimer contrast agents are significantly larger than typical MRI contrast agents. When injected intravenously, the dendrimer-based agents tend not to leak from the bloodstream into the body's other fluids. This makes for much clearer images of blood vessels. Furthermore, if a tumor has managed to permeate a blood vessel, the dendrimer will slip into the tumor's blood vessels and create a clear image of the tumor's growth.
Several companies are trying to develop dendrimer-based MRI contrast agents. Berlin-based Schering AG, for example, has been pursuing a polylysine dendrimer complexed with Gd(III) ions called Gadomer-17. Dendritic NanoTechnologies is developing a PAMAM dendrimer that encapsulates Magnevist within the dendrimer's hollows.
Ryan T. Hayes, Dendritic NanoTechnologies' director of business management, pointed out that years of research have established that anionic dendrimers have a low cytotoxicity over a broad range of concentrations. "When it comes to other nanotechnologies, like buckyballs and nanotubes, I think we're ahead of the curve, and that doesn't get a lot of attention," he said.
Industrial-scale dendrimer synthesis still presents some cost barriers to other applications like coatings and electronics, but some companies have found they can capitalize on the benefits of dendritic architecture by using hyperbranched polymers. Hyperbranched polymers are like the mutant offspring of dendrimers and linear polymers. These macromolecules branch like dendrimers, but the process of making them leads to a distribution of products.
"Hyperbranched polymers are a real mess," joked Peter E. Froehling, application development manager for Dutch start-up DSM Hybrane--a company that makes hyperbranched polymers. The mix may be too complex to use in pharmaceuticals, but Froehling contended that there are still plenty of profitable applications.
The hyperbranched polymer that Froehling helped develop at DSM is known as Hybrane. It's a hyperbranched poly(ester amide) based on a monomer made from reacting a cyclic anhydride with diisopropanolamine.
The resulting tertiary amide has two alcohol groups and one carboxylic acid at its termini. According to Froehling, polycondensation of this material occurs via an oxazolinium intermediate. This polymerization can be done in bulk without any catalyst under relatively mild conditions, he added. DSM Hybrane can vary or combine anhydrides and modify end groups to tweak Hybrane's properties (J. Poly. Sci. A 2004, 42, 3110).
HYBRANE HAS been a hit particularly with the petroleum industry to prevent the formation of gas hydrates--ice crystals that form around small hydrocarbons in oil. These ice crystals are remarkably stable at relatively high temperatures and low pressures, Froehling noted.
Gas hydrates plugging up an oil pipeline can cost the petroleum industry in excess of $1 million each day that production is shut down. The petroleum industry has tried to prevent hydrates from forming by drying and heating the oil as well as by adding thermodynamic inhibitors like antifreeze and methanol. None of these methods is ideal, but Froehling said that the latter is particularly problematic. "These chemicals are toxic and flammable," he noted, "and you don't want them sitting on your drilling platform."
Several research groups have reported that highly branched molecules such as dendrimers and hyperbranched polymers can have a profound effect on compounds' crystallization from solution. The DSM Hybrane scientists found that they could use certain types of Hybrane to suppress gas hydrate formation in oil pipelines. Furthermore, the compounds are biodegradable and nontoxic to sea organisms. Froehling noted that the oil industry has been using the technology since 2004.
The Swedish firm Perstorp also has been pursuing commercial applications with its line of hyperbranched polyesters known as Boltorn. "The chance that some of you used Boltorn today is quite high," remarked Anders Hult, a professor at Sweden's Royal Institute of Technology.
Boltorn hyperbranched polymers, based on the monomer 2,2-bis(hydroxymethyl)propionic acid, are used as additives in automobile seats. The additive increases firmness, Anders said, and is already used in 1.5 million cars. Perstorp also sells Boltorn for other applications such as ultraviolet curing and as resins for waterborne coatings.
Even though a number of companies have shown that they can make money with dendrimers and dendritic polymers, the technology still has a way to go in industrial circles before it reaches the heights it has achieved in academia (Prog. Polym. Sci. 2005, 30, 217). The commercial applications symposium was illuminating and well-attended, but most of the research presented at IDS-4 was carried out in academic labs.
Nevertheless, dendrimer champions like Tomalia argue that industry's interest has definitely been piqued. "Some major pharmaceutical companies are showing up at these conferences because they are sensing that something is brewing," he said.
"I think dendrimer science has begun the serious evolution from academic to commercial," Tomalia remarked. He and the rest of the dendrimer community will have a chance to see that evolution's progress again in 2007, when they meet for IDS-5 in Toulouse, France.
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