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Shaping drug delivery
More and better drugs are always in the pipeline, but they often come complete with new and nasty side effects. A McGill nano-technology research project may point the way toward a solution.
PHOTO: Claudio Calligaris
As part of a long-term research project, Otto Maass Professor of Chemistry Adi Eisenberg and professor of pharmacology Dusica Maysinger are working on an improved drug delivery system which could reduce the severity of side effects. They are using block copolymers, molecules which can assemble into microscopic structures that can take many different shapes and that have numerous potential, but currently untapped, applications.
The goal in this application, which uses block copolymer aggregates called micells, will be to aid the drug delivery of highly hydrophobic drugs. Given that the human body consists mostly of water, these drugs are problematic when a patient's body tries to absorb them.
Eisenberg explains that "in order to get these into someone's body, you have to resort to all sorts of tricks. We could, as an alternative, dissolve them into the core of a block copolymer micell. Micells could be very useful in drug delivery because they allow us to deliver highly hydrophobic drugs to the body.
"These drugs, especially the toxic ones, are a problem; they need to be above a certain threshold to do some good, but below the threshold at which a patient suffers severe ill effects. Because they are water insoluble, they are often absorbed by the body before they have a chance to dissolve, with a very adverse toxic effect. So determining just the right dosage is always tricky."
Micells would work by holding hydrophobic drugs in a tiny package, and allowing them to slowly leach out into the body.
"That way, you can actually deliver a much higher dose (than with traditional delivery systems) because it only leaks out of the package slowly. The micell helps you get it right, with the right concentration. You can give a toxic dose without doing any harm because it's only released in the body gradually."
Eisenberg is speculating about their use in humans, but his lab has successfully tested the system in animal experiments.
"We have had significant success in treating sciatic nerve crush, a neurological injury, in lab rats. We administered drugs using micells, and the animals healed about a week faster than with injection. Since the concentrations of drugs are easier to control with this method, the drugs are more effective, in addition to causing lower side effects." Eisenberg notes that in human patients, reducing side effects could also improve effectiveness. The reason is that severe side effects lead patients to cut corners, such as taking "vacations" from their drugs.
The next step - as an outgrowth of work described in a paper co-authored by Eisenberg and professor Discher of the University of Pennsylvania in the August 9 issue of Science magazine - will be to use vesicles, another form of block copolymer, for drug delivery. Eisenberg and Maysinger believe they can design them to deliver both hydrophobic and hydrophilic (water soluble) drugs at the same time in the body. The rate of absorption in the body could be controlled by varying the amounts of the drug stored; a larger amount would result in a faster absorption rate.
Drug delivery may be the first application to emerge from a fundamental research project launched 12 years ago. The NSERC-funded research is aimed at studying the shapes, properties and potential of aggregates of block copolymers. The potential is huge because of the vast variety of shapes they can take.
That potential was first hinted at in a 1995 article in Science by Eisenberg and his research group at McGill.
"A lot of people were already working on block copolymer micells," says Eisenberg. "We were the first to show, in that article, that you can systematically vary the morphology (structure) of block copolymers quite easily, through a number of factors, including the relative length of the chains, and the solvent in which it is dissolved." That morphology takes some exotic forms, including spheres, rods, platelets and tubules, all existing on the nano scale - typically one-thousandth of the width of a human hair.
That 1995 article inspired many other researchers to jump on the bandwagon; today many teams around the world are already working on applications.
The scope of the work expanded soon after the team started work in 1990. "It started as an examination of block copolymer micell spheres; we had no idea that there were so many other aggregates (shapes) that were possible. In the course of our experiments, we discovered all sorts of strange aggregates under the microscope. Once we realized that we could make and work with so many different aggregates, the whole field opened up." Each aggregate carries its own research interests and potential applications; for example, the development of conductors in nanoelectronics.
Eisenberg is collaborating with other university researchers, among them chemistry professor Ashok Kakkar of McGill, Alexander Kabanov of the University of Nebraska and Victor Kabanov at Moscow State University. However, he gives the lion's share of credit to the team members' respective graduate students.
"They are the front-line troops who are doing the most important part of the work. They make it happen; without them, we are nowhere."
Including the articles appearing in Science, Eisenberg's team has published approximately 100 papers on this research, in journals such as Macromolecules and The Journal of the American Chemical Society.