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Molecular umbrella’ could hold key to disease cures

If water-soluble drugs could be transported across this membrane to the interior of bacteria, fungi and cancer cells, scientists say, they could kill the cells by disrupting their DNA, their enzymes, or their vital activities.

Steve Regen, university distinguished professor of chemistry, believes he may have found one vehicle to do the trick.

The solution, he says, could come from molecules that show two faces to their environment--hydrophilic, or attracted to water, and hydrophobic, or repelled by water and attracted to oil.

Regen and Vaclav Janout, senior research scientist at Lehigh, are the first scientists to fashion "molecular umbrellas," which, by changing their orientation from hydrophilic to hydrophobic and vice-versa, show potential to introduce biologically active agents into the interiors of cells.

Regen and Janout have received funding for seven years from the National Institutes of Health to study molecular umbrellas. Recently, they received a four-year grant renewal for $1.2 million.

"This is a new mechanism for transporting agents across bilayers," Regen says. "Now we are designing molecular umbrellas that can act as catalysts, linking to the cell membrane and transporting several molecules across it."

A rainstorm brainstorm

Regen was attending a U.S. Department of Energy workshop in Seattle in 1996 when, by happenstance, he came up with his molecular umbrella concept.

"I was exhausted," Regen recalls, "so I took a day off and went to Olympic National Park and stayed at the Lake Crescent Lodge, a very informal lodge on the lake.

"I was sitting outside by the lake drinking a glass of wine. As is common in that part of the world, it started to rain, and I started to think of umbrellas."

The two-faced molecules in Regen’s umbrellas form columns that can be roughly likened to the covering of an umbrella. The hydrophobic outer face is compatible with the hydrophobic region of the cell membrane. The hydrophilic inner face embraces the hydrophilic drug, which is attached to the "handle" of the umbrella.

Regen and Janout currently believe that as the umbrella makes contact with the cell membrane, it closes, folding its hydrophilic inner face around the drug. The umbrella then eases its way across the hydrophobic membrane and into the watery cell interior, where the drug is released.

The "flipping" of the umbrella, Regen says, is triggered by the neighboring microenvironment. "The simplest interpretation of our data is that the umbrella is going across the cell membrane by a fundamentally new transport mechanism--that is, an umbrella mechanism."

`A stealth approach to ferrying drugs’

Regen and Janout have published several papers about their research in the Journal of the American Chemical Society. They have described how the tiny parasols can carry covalently attached peptides (made of an amino acid found in human cells) across the model membranes. By themselves, these same peptides will not cross the membrane.

The work of Regen and Janout has been described twice--in 2000 and again in May 2002--in articles in Science magazine, the world’s premier journal for science research.

The more recent article said Regen’s "stealth approach to ferrying drugs" represented "the first step toward delivering therapeutic DNA and RNA across the cell membrane."

Regen, who discussed molecular umbrellas on March 5 in Utah at the International Symposium on Recent Advances in Drug Delivery Systems, stresses that his research is fundamental and that applications will not follow for at least several years.

Recently, he began collaborating with David T.C. Chou, head of the biochemical pharmacology lab at the Memorial Sloan-Kettering Cancer Center. They are attempting to fit the molecular umbrellas with chlorambucil, an anti-cancer agent used to treat tumors in human leukemia patients. Chlorambucil decomposes in blood and other aqueous media, but when coupled with an umbrella, it shows a significant increase in water solubility and stability.

Regen and Chou have done laboratory studies with the coupled chlorambucil and are considering doing an animal study using one of the conjugates. The paper has been accepted for publication by the journal Bioconjugate, which is published by the American Chemical Society.

--Kurt Pfitzer
kap4@lehigh.edu

Posted on Monday, March 17, 2003

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