A solubility problem that has kept many potentially life- saving compounds from being used to diagnose and treat disease has been overcome through a new technology developed at the University of Rochester. The technology enables scientists to prepare a water-insoluble substance as particles so smooth and tiny that they will travel through blood vessels and organs without damaging them.
The work could have widespread applications in drug development, targeting and delivery as well as in diagnostic imaging.
A patent on the process was granted earlier this year to Michael Violante, associate professor and chemist in the radiology department at the University's Medical Center, and Harry Fischer, retired chair of the Department of Radiology.
The carefully controlled precipitation process produces particles that don't stick together and are uniformly spherical and smooth. This eliminates risks often associated with water- insoluble compounds, such as blood clots caused when particles clump together in the bloodstream, and damage to blood vessel walls caused by the particles' jagged edges.
So far Violante has applied this process to about 50 compounds, including six anti-cancer drugs, and is hopeful at least one of the drugs he is working on will be tested in humans soon. Successes include:
He is now working to formulate a drug isolated from a sea organism by a University of Arizona professor. In laboratory experiments it is very effective in killing tumors, but it has not been used because it has not been formulated.
Violante is currently working on several other compounds under contract with large pharmaceutical firms. Some of these drugs are already in use in humans, but Violante is looking for a better way to formulate them. Much of this work is done at Medisperse, a limited partnership created by Sterilization Technical Services Inc. (a Rochester firm where Violante is part- owner and vice president of research and development) and Unimed Inc., a New Jersey-based company which is marketing the technology to the pharmaceutical industry.
The process used by Violante allows him to create a suspension of particles less than one micron (one micron is one- millionth of a meter) in diameter apiece, well below the average 6-9 microns of red blood cells and the 4-5 microns of the smallest capillaries in the human body. The process produces uniform spherical particles (not crystals) and allows Violante to control the size of the particles.
This particle formation process was originally part of an effort by Violante and Fischer to develop a contrast agent for computed tomography (CT) and ultrasound scans to give doctors a better look at tissue. Their first formulation was the compound iodipamide ethyl ester (IDE), for use in CT imaging of the liver. IDE particles have been shown effective in CT and are now being tested for ultrasound liver imaging in laboratory animals by Violante, along with Robert Lerner, associate professor of radiology, and Kevin Parker, associate professor of electrical engineering. Several diagnostic imaging companies have expressed interest in the work.
Violante also hopes to use the process to target certain body organs. Targeting could help doctors deliver a more potent dose of drugs, which are often more toxic for one organ, such as the heart, than for other organs, such as the liver. When a drug distributes equally throughout the body, doctors must stay below that toxic level for the most sensitive organ. But if doctors can target the drug mainly to one organ or area of the body, perhaps higher and more effective doses can be administered while avoiding the high levels that would damage the sensitive organ.
Violante and Roy Steigbigel, a former University professor now at the State University of New York at Stony Brook, have also found that the injection of the IDE particles stimulated the effectiveness of certain cells in killing bacteria. This may open the door to a new class of drugs for use against a broad spectrum of infectious diseases. The pair was awarded a patent last year.
Violante's work is funded by the National Institutes of Health, the National Cancer Institute, STS and Medisperse.
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