Medical Device Daily Washington Editor

BETHESDA, Maryland — The National Institutes of Health wrapped up NanoWeek on Friday with a series of sessions that addressed how nanotechnology might help to drive the evolution of healthcare in the U.S. One researcher made the case that nanoscale constructs can do a lot to improve the delivery of drugs through the digestive machinery, thanks to attachment characteristics that improve absorption and reduce the needed load of drug. However, her discussion included the suggestion that drug elution in other anatomical locales, such as the coronary arteries, might also benefit from the use of small tubes.

Tejal Desai, PhD, director of the lab for therapeutic micro- and nanotechnology at the University of California at San Francisco (San Francisco) discussed the latest developments on how nanostructure platforms can deliver therapeutic agents in a targeted fashion. She said the question that drives the research at her lab is: "What can 'nano' do that cannot otherwise be done?"

Desai threw a glass of cold water on some of the hype behind nanotechnology with the observation that "we don't suppose that 'nano' is the answer to everything," but she posed the question, "are there challenges that can be addressed, such as chronic [drug] output?"

Most of the work done at the lab is focused on platforms for various applications such as cardiovascular disease and treatment of pathologies affecting oral, retinal and neuronal tissues. Desai said drugs can be encapsulated to allow them to reside in the body for a period of time before release, such as with the use of polyethylene glycol (PEG). One of the problems with conventional delivery approaches, however, is the repeat trips to the doctor or the risk of missed doses for patients who are forgetful or are weary of the side effects. In the case of interferon alpha (interferon), weekly administration is necessary because this anti-carcinogenic agent has a half-life of about a week.

Desai said her research implicitly builds on the property of zero-order release of a drug, which means in this case that drug release is not governed by the concentration of the drug in the delivery system. "If we create multiple windows or gates at the nanoscale, we can control the rate of delivery" regardless of the volume of the remaining payload, she said.

As the description implies, such a nano-device uses the size of the aperture to control the rate of flow. Desai noted that in contrast to classic diffusion, this single-file diffusion, provided by an appropriately structured gate in a nanoparticle delivery system, keeps the drug's serum or tissue profile more closely matched to the patient's need and hence sidesteps the peak-and-valley effect on concentrations engendered by more conventional approaches.

Desai noted that her lab has used lithography to "define pores within a bulk material" and that her lab employs a lot of silicates in this kind of research "because you get the best resolution" compared to other substrates. However, the idea can be applied to metals as well.

Using anodization, Desai observed, titanium can be engineered "down to 10 to 15 micrometers" and deliver drugs such as interferon, which she said has a molecular weight of about 19,000, or something as hefty as albumin, which weighs in at 66,000 moles. "We can deliver lots of different things" by tuning the size of the orifice, she said. This permits quick-release secretion of compounds "such as insulin, where we want rapid kinetics," but the technique can be used to release at a comparatively torpid pace a 90-day dose of interferon, too.

To the envy of the manufacturers of the first generation of fuel injectors, the load does not seem to plug up these nanosize delivery devices. "Even though we're at the nanoscale, they don't seem to clog or foul," Desai observed.

Nanoparticles, Desai said, can also be used to coat implants for drug release, including drug-eluting stents. She said her lab ran a test to compare the drug release characteristics of the Taxus, made by Cordis (Miami Lakes, Florida), to another method of releasing sirolimus from a titanium frame. She pointed out that engineers at Cordis tweak the thickness of the drug-bearing polymer to induce the desired rate and volume of elution, "but if you put something like this in a vascular environment, you not only release drug, but also polymer."

On the other hand, titanium nanotubes of about six microns in length "can control the drug's dispersion for about the same amount of time, 14 days," and such an approach would dodge some of the problems perceived to accompany absorption of the polymer. The titanium nanostructures remain attached to the stent's struts, which are all later overgrown by the artery's intimal layer.

"Oral drug delivery is the Holy Grail for drug delivery," Desai observed, a route taken for introducing everything from simple peptides, such as synthetic thyroid hormones, to more complex molecules, such as chemotherapeutic agents. Vehicles such as microspheres tend to disperse their loads throughout the colon rather than just to the surface of the colon, which is the objective for any drug intended to have a systemic effect. Such dispersion mandates the ingestion of a lot more drug than is really needed because of the loss, and raises the risk of side effects and adverse events.

Desai said the group at the lab decided to find out if they could embed one or more drugs inside a particle, which would then attach to the wall of the colon. "Our hypothesis is that if you can make a particle that intimately interacts with a cell surface, and that binding is of sufficient extent," the delivery can be more efficient and "can attenuate damage" to healthy tissues, she noted.

The delivery system, Desai said, might be a polymeric microparticle "that is planar and about 10 microns thick." A hydrogel-based mix would hold the therapeutic agent, and this construct is large enough that the work of shaping the materials into planar configurations can be done by lithography.

"You can make this in a variety of materials," Desai explained, and they can be built with multiple reservoirs or just one. The upshot of this is that a therapeutic intervention can introduce several drugs or only one. "We can get close to 50% of the drug to the target versus nominal amounts" delivered via other methods.

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