Imagine a particle that, once inside your body, sticks to the lining of your digestive tract. Ordinarily, such a particle would be either eliminated or pummeled into biochemical submission by your body's digestive arsenal--strong acids, enzymes, and rhythmic muscle contractions. But this particle is unusually tenacious. All of your body's efforts to slough it off just make it stick more tightly. A scary thought--unless, of course, the particle actually contains a timed-release drug.
Such a drug delivery system is showing great promise in the laboratory of Dr. Edith Mathiowitz at Brown University in Providence, Rhode Island. Dr. Mathiowitz and her coworkers have discovered how to make tiny, drug-filled beads that, when fed to rats, stick to intestinal tissues and slowly erode to deliver the drugs into the bloodstream. Their work strongly suggests that the technique could be used to deliver drugs orally that are currently administered only by injection.
The delivery system is not limited to the digestive tract, and in the future it might be used to administer a wide variety of substances, including DNA-based vaccines, cancer chemotherapy, hormones, and gene therapy. Most immediately, the scientists are working to optimize the method to treat inflammatory bowel disorders such as ulcerative colitis, Crohn's disease, and peptic ulcers.
The researchers describe their findings in the March 27 issue of the journal Nature.
"The exciting thing is that with a similar delivery system, we were successful in delivering a small molecule such as dicumarol (an anticoagulant); proteins, such as insulin; and also huge molecules such as DNA," said Dr. Mathiowitz, lead author on the paper. "So we showed this is quite a general mode of delivery, and could be used for many kinds of drugs."
The novel aspects of the work relate to the unorthodox material and the extremely small size of the microspheres the scientists use.
Researchers often seek to increase drug absorption by using materials that are bioadhesive, meaning that they stick to their target rather than flowing straight through the body. "The current dogma is that the best bioadhesives are hydrogels, which are sticky, watery, gelatinous materials," said Jules Jacob, second author on the paper. Yet the researchers found that in some cases, certain thermoplastics--hard substances not unlike the plastic used in ball-point pens--are significantly better bioadhesives.
These polymers appear to be ideal compounds for drug delivery. They're biocompatible, which means the body won't reject them. They're biodegradable, so they're metabolized into non-toxic compounds. And each type of thermoplastic has different bioadhesive properties.
"If we want short release, we might use one polymer; if we want longer release, we might use another polymer," Dr. Mathiowitz said. "We can tailor the release and the bioadhesion for specific applications."
In their current study, insulin delivered in microspheres lowered blood sugar levels within two hours, dicumarol remained for in the bloodstream up to three days, and DNA was incorporated into cells and produced a new protein within five days.
The researchers believe that the success of their work is partially due to the small size of their beads, which ranged from 0.1 to 5 microns in diameter. (Some human hair is about one micron thick.) The scientists controlled the size of these microspheres using a new technique they developed called PIN, for phase inversion nanoencapsulation.
As promising as their results sound, the researchers are quick to point out that they are already a step or two ahead.
"The Nature paper only covers the first generation of polymers," Jacob said. "We have at least two other classes of materials under development that have enhanced bioadhesive properties." These new materials, when combined with their existing repertoire of thermoplastics, allow the scientists to better customize the release--from hours to weeks--of their drug delivery microspheres.
In addition to developing new materials, the scientists are working to optimize targeting of the microspheres to specific tissues or cells in order to treat diseases such as cystic fibrosis or cancer.
Although the work will require years to refine for clinical use, the researchers' results so far indicate that the technique may not only enable oral delivery of drugs that currently are administered only by injection, but may also permit better absorption of some orally administered drugs.
The graduate students who were critical to the project are Yong Jong, Gerardo Carino, Donald Chickering, and Camilla Santos.
This research was partially supported by the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health that supports basic, non-disease-targeted research.
Mathiowitz E et al. Biologically Erodable Microspheres as Potential Oral Drug Delivery Systems. Nature 1997;386:410-414.
Dr. Edith Mathiowitz, Jules Jacob, and coworkers
Artificial Organ Laboratory
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