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MIT scientists and colleagues have created microscopic, spherical "containers"-for drugs, medical-imaging agents and more-that can be injected intravenously and will stay in the bloodstream for several hours.
The work is important because spheres created by other techniques are eliminated by the body within seconds or minutes after intravenous injection, preventing their use in many applications. They are simply gobbled up too quickly to do any useful work.
In addition to longevity, the new spheres, which have been tested in mice, display several other desirable characteristics:
- they are biodegradable and very small (diameters of 90-150 nanometers, or billionths of a meter);
- they can be freeze-dried and then easily redispersed in water solutions,
- they contain a high amount of drug or other agent in each individual sphere.
Moreover, the spheres are extremely efficient at absorbing the drug or agent in the manufacturing process.
Until now it has proven extremely difficult to develop particles with all of these qualities. "We can do this, and we can do it in a one-step procedure," said Robert S. Langer, Kenneth J. Germeshausen Professor of Chemical and Biomedical Engineering in the Department of Chemical Engineering. The work was reported in the March 18 issue of Science.
The nanospheres (so named for their small size) and the procedure to produce them have been exclusively optioned to the start-up company Acusphere for medical imaging and certain other medical fields of use.
For medical-imaging applications, microscopic spheres could be used to carry image-enhancing agents to the tissue or organ of interest. Several research groups are developing spheres for this purpose, but the spheres are quickly removed by the body. For example most spheres containing ultrasound contrast agents "are cleared in about 20 seconds, and that prevents you from getting most images," Professor Langer said. "Partly as a consequence of this problem, no ultrasound contrast agents are yet approved for clinical use in the United States."
The new nanospheres consist of a polymer core-in which a drug or other agent can be dispersed-that is chemically coupled to another polymer that provides a protective coating. The drug or agent is then released over time as it diffuses through the coating or as the nanospheres break down.
The coating is the key to the nanospheres' longevity in the blood. The researchers found that it apparently helps prevent recognition and subsequent destruction of the spheres by the cells in the body that scavenge foreign particles.
In an experiment to this end, the scientists injected coated and non-coated spheres into mice. "Only five minutes after injection, 66 percent of non-coated particles were removed by the liver, while less than 30 percent of. coated particles were captured by the liver two hours after injection," they report in Science. "We further observed that after five hours, accumulation of. coated spheres by the liver did not exceed 30 percent."
The scientists also explored the new nanospheres' encapsulation properties. These include how much drug can be contained within individual spheres and the spheres' entrapment efficiencies (how much of the bulk drug added to the manufacturing process is actually incorporated into the spheres). They received good results in both cases.
For example, when the drug lidocaine was used, "we found that almost half of each nanosphere was composed of drug," Professor Langer said. (A drug "loading" of 30 percent is considered good.)
Entrapment efficiencies for lidocaine were also high. "More than 95 percent of the initial drug in the encapsulation solution was entrapped," they report. Similar results were observed for other drugs.
The scientists envision a number of applications for the coated nanospheres. For example, they write, "antibodies could be attached to [the coating], potentially forming highly specific, targetable entities to desired tissues." They conclude that "with further study, these nanospheres may be useful in a variety of drug delivery, medical imaging, gene therapy or other applications."
In addition to Professor Langer, authors of the Science paper are Drs. Ruxandra Gref, Yoshiharu Minamitake and Maria Teresa Peracchia, all visiting scientists at MIT (Dr. Gref is now at the Ecole Nationale Superieure des Industries Chimiques in France), and Drs. Vladimir Trubetskoy and Vladimir Torchilin of Massachusetts General Hospital-East.
A patent has been filed for the MIT nanospheres and the procedure to produce them. The work was supported by the NIH and a Lavoisier grant from the French Foreign Affairs Ministry.
A version of this article appeared in the April 6, 1994 issue of MIT Tech Talk (Volume 38, Number 28).