June 15, 2005 (Vol. 25, No. 12)
Diverse Approaches and Applications Illustrate the Technology’s Versatility
Nanotech, the manipulation of individual molecules to produce materials with new and unique structural properties, is poised to become a major force in advanced materials research that will affect areas of research as diverse as drug delivery, electronics, and even cosmetics, according to speakers at the “NSTI Nanotech 2005 Conference” held in Anaheim, CA, last month.
A few products are already on the market, like ZinClear, transparent zinc-oxide nano-sunscreen by Advanced Nanotechnology Limited (www.apt-powders.com). Most, however, are looking at commercialization in five or more years. “Successes will be few and far between,” according to Keith Larson, managing director, Intel Capital. “Those most likely to be successful will approach nanotech as a way to improve an existing product.”
“Nanotechnology is an enabling technology, not the product itself,” emphasizes Amit M. Kulkarni, Ph.D., research scientist at GE Global Research Center.
Ambri Technology (www.ambri.com.au) is a case in point. It is developing its Ion Channel Switch (ICS) technology for a wide range of biosensor applications, including point-of-care diagnostics, bacteriological detection, food testing, environmental monitoring, veterinary diagnostics, and drug discovery lab diagnostics systems. The immediate focus is on cardiology, bacteriology, and respiratory applications.
In designing the ICS technology, “We copied nature,” according to Bruce Cornell, Ph.D., founder and chief scientist. “The ICS forms by self-assembly of lipids.” The system is designed as a membrane two molecules thick, with a thin layer of gold (insulated by the surface lipid), an ionically conducting reservoir space to store ions that have crossed the membrane, gramicidin ion channels (resembling pipes) that traverse the membrane, and receptors that decorate the membrane to recognize target molecules.
“We have the equivalent of the inside of a cell. The membrane does not conduct ions when the channels are misaligned. Only when aligned are the ions conducted,” Dr. Cornell emphasizes. Because recognition of a diagnostic marker is read as a change in an electrical current, the ICS membrane may be interfaced with a computer chip.
The system offers “direct electrical reading, array optics that equal or exceed the reliability of electrical systems, and miniaturization,” Dr. Cornell says, and is inexpensive. It allows multiple tests to be performed simultaneously on a single, disposable chip that can be read on a small hand-held reader and integrated into many different platforms.
StarPharma (www.starpharma.com), also represented at the NSTI meeting by Dr. Cornell through his role in Invest Australia, is developing dendrimer nanotechnology to develop “defined and biocompatible nanoscale objects built from the bottom up.” VivaGel, its nanotech drug to prevent the sexual transmission of HIV, was reportedly the first nanotech drug in the world to enter human trials.
StarPharma’s dendrimers may be designed for polyvalent interaction. They are stable, safe at therapeutic doses, efficacious against a wide range of diseases, and cost-effective to manufacture. The benefits of this drug delivery method, according to the company, include increased rigidity, which makes more predictable placement of surface groups possible and thereby results in more specific targeting and enhanced control of surface functionality.
GE Global Research Center is using bionanotech to develop advanced personalized medicine to the point where molecular imaging can be used to track and verify disease, and molecular therapeutics can prevent and treat disease.
“For diagnostics and molecular imaging, we can now get anatomical, organ-level information. For the future, we want cell and molecular level information on function and physiology. That’s where nanotech comes into play,” says Dr. Kulkarni.
Concentrating particles of gadolinium I chelates within nanoparticles, Dr. Kulkarni says, enhances image signals and bandwidth control. Also, “depending on size, small nanoparticles can cross the blood-brain barrier, medium-sized nanoparticles can penetrate tissues, and large particles (about 80 nm) can be taken up by the liver and spleen.” Therefore, researchers must consider the size and shape of the nanoparticles they are using.
The superparamagnetic iron oxide particles that GE developed range from 10100 nm. Its gadolinium-filled fullerenes range in size from 15 nm and its quantum dots of cadmium-selenium are 420 nm in size.
GE is making 5-nm nanoparticles with a size variation per batch of 115%, 1020 nm hydrodynamic particles, and a variety of chemistries for negative or positive charges. “Uptake in cells depends on particle size and coating type,” Dr. Kulkarni says. “The GE-A 60-nm nanoparticles have a fast uptake of about 20 minutes and almost total clearance. The 20-nm GE-B and the 12-nm GE-C nanoparticles each have a slower uptake.”
Those sizes themselves pose some challenges because different sizes have differences in pharmacokinetics and pharmacodynamics, making it an issue of stability versus aggregation in aqueous formulations. Nanostructures behave differently than their larger versions, forcing researchers to consider a broad range of issues in a slightly different context.
“Biodegradability, because of uptake to RES organs, is a huge issue,” Dr. Kulkarni points out. “They are taken up quickly. Nanoparticles can be target-specific, but you also get nonspecific binding,” making toxicity and renal clearance key concerns. “We need a nontoxic degradation path,” he says, and nanostructures that can be manufactured in bulk at a low cost. “You’re asking a lot of these particles.”
About 20% of GE’s projects are dedicated to advanced technology, according to Dr. Kulkarni. The GE Global Research Center has 50 scientists developing nanotech for advanced materials, consumer and industrial engineering, healthcare, infrastructure, and transportation projects. There are five structures under investigation: nanotubes and rods, nanoparticles, hybrids, ceramic, and nanostructured metals.
Within the biosciences division, GE is focusing on medical diagnostics, protein separation, and drug development systems, which often complement its work in digital imaging technologies and contrast agents.
The pharmaceutical industry aims to develop a multifaceted nanoplatform that incorporates imaging and targeting molecules as well as therapeutic and reporter molecules. Still in the early development stage, Pfizer’s (www.pfizer.com) researchers are “trying to assess the current state of the art and promising avenues to develop a long-term strategy,” according to Mostafa Analoui, Ph.D., senior director, global clinical platforms, Pfizer Global Research and Development.
One potential application of such technology is using superparamagnetic iron oxide nanoparticles as contrast agents for studying vascular walls. This method lets researchers see the morphology and tissue types, as well as “where the drug is and how it’s interacting with the tissue,” Dr. Analoui says. Consequently, activity can be monitored long before the walls thicken and plaque forms.
Midterm (510 years) expectations from nanotechnology involve portfolio enhancement by reformulating active compounds with nanotech formulas as delivery mechanisms. Ten-plus years out, Pfizer envisions combining diagnostics and therapeutics, developing targeted delivery and release for a practical clinical system, releasing new classes of drugs that act on old targets, and increasing use (industry-wide) of in silico drug development and in vivo diagnostics that provide quantitative data “as frequently as possible.”
“When researchers think of nanomaterials, diamondoids are often an afterthought, behind Buckminster fullerenes, quantum dots, and nanotubes,” according to Frederick Lam, Ph.D., director of business development at MolecularDiamond Technology (www.moleculardiamond.com), a business unit of Chevron Technology Ventures.
Diamondoids offer some highly desirable attributes, including extreme hardness, wear resistance, low compression, broad optical transparency, and great resistance to chemicals and to corrosion.
Since diamondoids were discovered in 2003, MolecularDiamond has isolated at least 50 distinct chiral structures, and “many exist with alkyl groups attached,” Dr. Lam notes. “We’ve synthesized bromines, amines, hydroxyls, ketones, and carboylic acid, and have compounds in testing for neuroprotection, oncology, in vitro electrophysiological assays, and other applications.”
They are easy to synthesize, purify, and analyze, have great diversity, have a molecular weight of less than 500 Daltons so they may be orally administered, and have rigid structures, which increase bioavailability, Dr. Lam says. They also have robust carbon pathways and may penetrate the blood-brain barrier.
Because these nanostructures have no heavy metals, they may be particularly useful in drug delivery and “probably will clear the body easily,” Dr. Lam says. They may be used as scaffolds or added to polymers, used in bio-labeling, as targeting agents, and in bio-implantable devices. “They have been made into smooth films and are inert to chemical reactions,” he adds.
SurModics (www.surmodics. com) is developing nanotechnology as a possible drug delivery matrix. Early development is focusing on drug delivery coatings combined with medical devices, such as drug-eluting stents, and also on developing coatings for high throughput assays and as surfaces on which to grow mammalian cell culture.
PhotoLink chemistry forms the basis of the technology. In it, hydrophobic molecules are exposed to UV light to excite the substrate. Two radicals are formed, which bond to the substrate in a covalent bond. Applications include medical devices, cell and tissue culture, biosensors and MEMS, microfluidics chambers, nanosystems, and regenerative medicine.
Boston Scientific (www.bostonscientific.com) is exploring the power of nanoscale characterization. If you go to the microphase separation of lots of polymers, “controlling the nanophase separation can affect biological interactionalthough not necessarily medical implications,” according to Michael Helmus, Ph.D., vp, advanced biomaterials at Boston Scientific.
In its drug-eluting stent, paclitaxel is incorporated into a polymer of SIBS polystyrene. “The drug is biostable, vascular compatible, and you can incorporate drugs at the right release rate,” Dr. Helmus says. At 8.8% paclitaxel, using 2030 nm particles, “it appears to partition in the styrene phase.”
Subsurface morphology reveals that subsurface distribution of paclitaxel is like that on the surface. As the concentration of paclitaxel increases from 8.8% to 25 35%, “the surfaces all look the same, but release rates increase with the percentage of the drug incorporated into the polystyrene.” Furthermore, the surface particles release more rapidly than the internal particles, and behave as discrete particles with a long-term retention rate.
In the medical field, enhanced function and biocompatibility are key attractions for nanotechnology, but new paradigms may be necessary, Dr. Helmus says. Using nanotechnology to develop efficacious therapeutics and diagnostics will require the early collaboration of researchers with clinicians, and an understanding of the clinical environment.
“Toxicology and biocompatibility must be determined in preclinical studies,” Dr. Helmus advises. Biocompatibility, for example, should be built into the product upfront because nanoparticles behave differentlyand have different toxicologiesthan larger versions of even the same particles.
Because nanotechnology is such a new field, developmental standards are not yet in place. The ISO, for example, has at least 19 different ISO standards for medical devices, which may apply to nanotechnology, but are not specific to it. The FDA is studying nanotechnology, but “there are no standards yet,” Dr. Helmus says. For the time being the FDA recommends adhering to current preclinical safety assessments.
“Many nanodevices will be viewed as combination devices,” he continues, requiring that they meet most drug requirements as well as device requirements. Eventually, new models coordinated among the FDA, Centers for Disease Control and Prevention, Medicare, Medicaid, and National Institutes of Health will be needed to make requirements in the U.S. more transparent.
“Although we’ve made significant progress, there are more challenges ahead,” Dr. Analoui concludes.