Special Delivery

Courtesy of Nadine Barrie Smith PATCHING THROUGH: The ultrasound patch, weighing less than 22 grams, is an array made from up to four cymbal transducers, encased in a flexible polymer. This array's dimensions are 37 x 37 x 7 mm. It can be made thinner. Proteins represent the largest class of biotech drug ap-provals, and the numbers will continue to rise as work with the human genome sequence proceeds. Figures from 2000 show that 86% of 77 approved biotech medicines are proteins, with hundreds more in the pipeline.1 Yet, delivering proteins--that is, getting the drug into the body so that it retains its functionality--is problematic. Pills, by far the preferred method, do not work without some fancy engineering to shepherd the proteins safely through the gastrointestinal tract. And injections are literally a pain. It's no wonder that over 300 companies are designing novel drug delivery systems, according to a report from market research firm Frost and Sullivan.2 Vectors, buckyballs, nanotubes, and microchips are just some devices being harnessed to deliver drugs. And every bodily surface is fair game--nose, lungs, skin, gut, even the eye. Take insulin, for example. Since 1922, patients with diabetes have been self-administering insulin using a 150-year-old technology: the hypodermic needle. But as the incidence of diabetes rises, so too has interest in designing better delivery routes. In the next few years, patients could be choosing among a variety of delivery methods, including implantable pumps, encapsulated islet cells, insulin inhalers, and patches. Freeing patients from the pain and inconvenience of injecting themselves is only one reason for this interest; better control of glucose levels would also have long-term health benefits. In addition, the small protein (insulin monomers are only 6000 daltons) is a good starting point for developing protein delivery methods. And then there's the small matter of a $4 billion market in the US alone. A brief survey of what drug companies are planning provides a peek into patients' drug cabinets of the future. PUMPING INSULIN Patients with diabetes have only one choice other than injections. Of 100 million patients currently requiring insulin, approximately 200,000 use a pump, says Deanne McLaughlin of Medtronic MiniMed, a pump manufacturer in Northridge, Calif. The device delivers a slow, continuous stream of insulin through a tube inserted under the skin, which mimics baseline insulin levels. When more insulin is needed, the patient pushes a button to deliver a bolus of insulin. The pumps require a bit of maintenance, and patients still need to check glucose levels, but they are more convenient than injections, and they control glucose levels better. The next generation of pumps will do a lot more, says McLaughlin. Last year, MiniMed, in collaboration with French re-searchers, reported that they had test-ed a "closed-loop" (artificial pancreas) system that monitors glucose levels through an implanted sensor, and delivers an appropriate amount of insulin in response from an implantable pump. BREATHE IN The lungs present an inviting site for drug delivery, with over 60 yards of surface area (larger than a tennis court) and access to a rich capillary bed. Accordingly, all the major insulin suppliers have partnered up with inhalation experts--yet patients wait. A combination of factors presently hold up progress, says Harvard University bioengineer David Edwards. For one thing, prior to 1990, no one had experience delivering proteins in this fashion, nor did a regulatory framework exist for assessing safety and efficacy of inhaled proteins. Moreover, to get efficient insulin delivery, researchers devised complicated devices, which has slowed the review process. Edwards approached the problem from a different angle. Rather than redesigning inhalers, he engineered insulin particles so that they could be easily dispersed, enabling him to use a simpler delivery device. His objective was to design particles small enough to get through the ciliated epithelia, located at the top of the airway, which sweeps inhaled particles away, and yet large enough to avoid attracting the attention of macrophages. Edwards exploited a metric he calls aerodynamic diameter, a function of both particle size and density, which predicts how much of the insulin will reach the lung's lower portions.3 Edward's design has been incorporated into an inhaler by Cambridge, Mass.-based Alkermes, but clinical trials are moving at a snail's pace. The number of patients needing insulin and the duration for which it will be required are both increasing, yet the Food and Drug Administration has taken a conservative stance in its review of new insulin delivery technologies, says Edwards. "The FDA is saying, 'At least injections are working.' They need us to prove safety beyond any reasonable doubt. So the bigger challenge right now for the industry is stamina. The trials have become so long. The question is can everyone hang in there," he says. SMALL WORLD Taking a page from the integrated circuit industry, biomedical engineer Tejal Desai, Boston University, has designed nanoporous biocapsules for insulin delivery.4 These tiny insulin-producing devices, which contain islet cells, are surrounded by a semipermeable membrane. The pores, which average 20 nm, are big enough to allow glucose and insulin, but not antibodies, to cross freely, which puts the capsule outside the reach of the body's immune system. This allows Desai to use islet cells from any source without fearing rejection by the patient. The capsules would be implanted either interaperitoneally or subcutaneously, not more than a few hundred microns from a blood vessel. Because of the uniform pore size, the biocapsules can deliver a constant amount of insulin over a long period, while also responding dynamically to changes in glucose levels, she says. "Instead of having what a lot of the devices currently being used have, a burst effect, where initially there is a very high rate of release, and then it trails off, this enables us to deliver in a constant, easily controlled dose." So far, Desai has worked on small- animal models, but in collaboration with the Columbus, Ohio-based firm, iMEDD, she is scaling up the project for humans. Larger animals require more cells, and she is exploring various capsule designs to accommodate this. GETTING UNDER YOUR SKIN The skin, with its tight junctions and largely impenetrable outer layer (stratum corneum), presents an even greater challenge than the lungs. Because of the huge success of skin patches--many drugs from contraceptives to nitroglycerine are delivered through them--various approaches are being taken to modify patches for delivering macromolecules. ALZA, of Mountain View, Calif., the first to introduce a transdermal patch, has two second-generation patches in the works. The Macroflux, a microprojection array, creates tiny channels in the skin, and delivers proteins that coat the projections through the barrier into the epidermis, which abuts the capillary bed.5 Another, the E-TRANS, uses electric currents to force molecules through the skin. So far, ALZA scientists have used E-TRANS on small molecules, but by changing the voltage, they say they can apply it to molecules of any size. In another approach to transdermal delivery, ultrasound is being tested to reversibly disrupt the skin by cavitation (bubbles). The first experiments used laboratory-scale sonicators to create the force, but Pennsylvania State University engineers have miniaturized the system by arraying tiny cymbal-shaped transducers on a 11/2 inch square patch. Using this device, engineer Nadine Barrie Smith reports that they have delivered therapeutic levels of insulin to rats.6 Pumping, breathing, patching--unconventional ways of delivering insulin that, in time, could be considered status quo. Laura DeFrancesco (defrancesco1@earthlink.net) is a freelance writer in Pasadena, Calif. References 1. J. Van Brunt, "The Payoff: Betting on protein drugs," Signals, 2000; www.signalsmag.com 2. "Emerging technologies in drug delivery: Frost and Sullivan, San Jose, Calif., Dec. 12, 2002; www.frost.com 3. D. Edwards et al., "Large porous particles for pulmonary drug delivery," Science, 276:1868-71, 1997. 4. T.A. Desai, "Microfabrication technology for pancreatic cell encapsulation," Expert Opin Biol Ther, 2:633-46, August 2002. 5. J.A. Matriano et al., "Macroflux microprojection array patch technology: a new and efficient approach for intracutaneous immunization," Pharm Res, 19:63-70, 2002. 6. S. Lee et al., "Ultrasound mediated transdermal in vivo transport of insulin with low profile cymbal arrays," Proceedings of the IEEE 2002 Ultrasonics Symposium, Munich, Oct. 8-11, 2002. Courtesy of David Schaffer GETTING SMARTER ON DRUG DELIVERY For many drugs to work, they must enter the cellular cytoplasm. But this requires dodging the body's defenses, which work to keep foreign molecules out. Crafty scientists are now harnessing the tricks of viruses to evade cellular defense mechanisms. "We're trying to mimic the way biology has solved the problem," says Pat Stayton, a bioengineer professor at the University of Washington, who developed a completely synthetic, pH-sensitive 'smart polymer' that allows almost any molecule, including antibodies, DNA, and RNA, to pass into the cytoplasm unscathed.1 Cells import large or hydrophilic macromolecules (including many drugs) across their oily, hydrophobic membranes by encasing them in vesicles that bud off from the outer membrane and form endosomes. "They take things inside of the cell, but they aren't really inside because they are always encapsulated in a membrane," says Stayton. The endosomal pH starts at physiological levels (~7.4) but gradually drops to about pH 5.0 as the endosome transforms into a lysosome. If a drug can't make its way out, it gets degraded. "Viruses [have] escaped that pathway by evolving pH-dependent proteins that are inactive as they circulate through the body, but become active once they are taken up into an endosome," explains Stayton. It's these pH-sensitive proteins that allow viruses to overcome the key barrier--getting out of the endosome and into the cytoplasm. David Schaffer, assistant professor of chemical engineering at University of California, Berkeley, says other groups have used natural, pH-sensitive, viral peptides to poke holes in membranes, but they have encountered aggregation problems because of peptide hydrophobicity. Schaffer says Stayton's approach is the "first sophisticated effort, completely with synthetic molecules and chemical groups, to develop a mechanism for cell surface binding and endosomal escape to deliver a payload into the interior of a cell." James Hagstrom, vice president of scientific operations at Madison, Wis.-based Mirus, believes Stayton's technology could address a key bottleneck in gene transfer, because DNA-containing vectors are largely internalized through endocytosis and must enter the nucleus. However, he says, "A key aspect that must be addressed is how to maintain membrane disruption activity of the smart polymers when they are associated with other polymers," such as the cationic and anionic polymers often used in gene delivery. --Mignon Fogarty 1. P. Stayton et al., "A biomimetic pH-responsive polymer directs endosomal release and intra-cellular delivery of an endocytosed antibody complex," Bioconjug Chem, 13:996-1001, 2002.

Special Delivery

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Courtesy of Nadine Barrie Smith
PATCHING THROUGH: The ultrasound patch, weighing less than 22 grams, is an array made from up to four cymbal transducers, encased in a flexible polymer. This array's dimensions are 37 x 37 x 7 mm. It can be made thinner.