ON The University of Wisconsin-Madison
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FALL/WINTER 2001-02

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Engineering approaches to drug design and delivery

More than 80 million people in the United States are stricken with some type of neurological disorder. These range from Alzheimer's and Parkinson's diseases to brain cancer, stroke and migraine headaches. Advances in chemical syntheses and medical biotechnology have given rise to a number of promising small molecule pharmaceuticals, and have expanded the ability to probe new frontiers of protein and gene medicines. However despite these advancements, none of the aforementioned central nervous system diseases has a cure and few have effective treatments. One of the largest stumbling blocks to treatment is that orally or intravenously administered drugs seldom reach their brain target.

Although over 400 miles of blood vessels perfuse the human brain and provide an extraordinary surface area for drug transport, non-invasive delivery of drugs to the brain is severely hampered by the blood-brain barrier. This so-called barrier formed by the blood vessels is highly impermeable to solutes in the bloodstream and limits the brain uptake of administered drugs. Even for the smallest molecules, simple diffusion provides limited transport of medicines across this barrier: nearly 98 percent of all small molecule pharmaceuticals and all protein and gene medicines fail to cross this barrier. In addressing this problem, we are using first principles in conjunction with cutting-edge biotechnology to engineer strategies that result in non-invasive drug delivery to the brain.

The blood-brain barrier, like all living cells, is a complicated, dynamic system consisting of 30-40,000 proteins collectively performing specialized functions. Our lab is poised to uncover the expression patterns of these genes and their coordinate protein products as they apply to non-invasive drug delivery to the brain. We are using microarray technology to search for genes that are specifically expressed at the blood-brain barrier and normally function in the active transport of nutrients to the brain. We can then design artificial substrates for these transporters and link them to a drug payload. These conjugates, acting as molecular Trojan horses, can then gain entry. We are also designing robust technologies that can discriminate the protein contents of the cell. This information is complementary to that acquired using the gene microarrays and can lead to the discovery of novel drug delivery targets. These studies will also reveal mechanistic insights about molecular transport systems so that delivery strategies can be rationally optimized to overcome barriers to brain drug delivery.

By Eric Shusta

 

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Date last modified: Friday, 09-Nov-2001 11:00:00 CST
Date created: 08-Nov-2001 17:01:00