Purdue researchers visualize cellular drug delivery

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A Purdue University researcher has developed a technique to visualize drugs being released within cancer cells to improve targeted drug delivery. The discovery was made through the use of an imaging technique to visualize mechanisms at the cellular level, according to a release.
   
"As a general strategy, the indiscriminate delivery of drugs into every cell of the body for the treatment of a few specific pathologic cells, such as cancer cells, is a thing of the past," said Philip Low, professor of chemistry, and founder and chief science officer of Endocyte Inc., a Purdue Research Park-based company. "Most new drugs under development will be targeted directly to the pathologic, disease-causing cells, and we have shed light on the details of one mechanism by which this is achieved."
   
An understanding of the cellular process that leads to the release of targeted drugs is a major advancement for the field, Low said.
   
"This will help others interested in targeted drug therapy," said Low. "The knowledge applies not only to the treatment of cancer. The understanding of how to deliver and unload a cancer drug can be extrapolated to all sorts of other diseased cells.
The uptake pathways are similar in cells involved in arthritis, multiple sclerosis, psoriasis and Crohn's disease."
   
Low and his team developed a color-coded method to visualize the cellular mechanisms. The team developed this method using a technique called fluorescence resonance energy transfer imaging.
   
"The drug turns from red to green when it is released inside the cell, clearly illuminating the process," Jun Yang, a postdoctoral research associate in Low's research group. "This is the first optical method to be developed to monitor this release. The main promise of this method is that it does not damage the cells being studied. Therefore, we are able to observe the process under true physiological conditions and watch it right as it is happening."
   
In targeted drug therapy, drugs are linked to molecules that are used in excess by pathologic cells, in order to transport drugs directly to the targeted cells while avoiding normal cells.
   
"It is desirable to have the drug released from the ligand, folic acid, once the folate-linked complex enters the cell," Yang said. "This 'conditional drug release' is usually realized by attaching folate to the drug through a linker that falls apart inside the cell. There were several linkers in common use, but with mixed efficiency. In this study we undertook to interrogate the full details of this breakdown process."
   
Yang examined receptor endocytosis, the process by which cells absorb materials — such as a drug attached to folic acid — that have been captured at special sites, called receptors, on the cell surface. The compound is then broken down and processed, releasing the drug.
   
One of the key mechanisms of this breakdown is disulfide reduction, which involves the breaking of chemical bonds. The research showed that disulfide reduction occurred even when such components were removed from the process.
   
The mechanisms and other details involved in the release of drugs within a cell had been under debate for several years, Low said.
   
"This is the definitive statement on how drugs are released within a cell," he said. "We will use this knowledge to develop better receptor-targeted drug therapies to treat cancer and other diseases."
   
This research, funded by Endocyte, will be detailed in the Sept. 12 issue of the Proceedings of the National Academy of Sciences.