Toxin tricks could help deliver drugs

 

Posted: 04 April 2012

Imagine a delivery person arrives at your house with a package. You open it up, and, depending on what it is, you decide where it will go in the house. It’s a book? That goes on the shelf. New clothes? Into the wardrobe. But if it’s something you don’t want, or that you don’t trust, it goes into the bin.

Similarly, when a molecule or compound gets delivered to a cell in your body, it is trafficked to a location in the cell’s interior. And in the case of some molecules, they get routed into the cellular bin, a compartment called the lysosome.

This can be a problem when you want to deliver a drug or therapeutic agent to a cell, explains Professor Jeremy Simpson, Professor of Cell Biology at UCD School of Biology & Environmental Science. “Once the molecule gets inside cells the default pathway is to the lysosome, where everything is destroyed and recycled,” he explains. “And if you are trying to deliver a sensitive molecule, that could be disadvantageous.”

"One way to try and get over this hurdle is to deliver greater numbers of the molecules to the cell, but that’s an expensive process and one that can push up the risk of side-effects for a patient," says Professor Simpson. Wouldn’t it be better to deliver the drug molecules in a way that means they don’t get trafficked to the bin?

It turns out that some toxins have already cracked that problem - molecules such as ricin (which was infamously used to assassinate Georgi Markov in the 1970s with a stab from a loaded umbrella tip) and some food poisoning agents made by bacteria can avoid getting shuttled to the bin.

To better understand this alternative trafficking process, Professor Simpson and his team are working with human cells growing in the lab. They are painstakingly knocking down each of 22,000 genes one by one and looking at how this affects the fate of the E. coli Shiga-like toxin when it gets taken up.

“We are working with a safe version of the toxin and we have fluorescently labelled it so we can visualise it as it passes through the different compartments of the cell,” explains Professor Simpson.

Manually trawling through the data from millions of cells would be a mammoth task, so the project is using an automated microscopy system that acquires images of the cells and analayses them.

They are currently doing an initial genome screen of the cells challenged with the toxin to narrow down the search for genes involved in its trafficking. “We want to get the 22,000 genes down to a more manageable number of interesting things,” says Professor Simpson.

He is also collaborating with Professor Kenneth Dawson and Professor Gil Lee to visualise what happens to cells when you deliver fluorescently-labelled nanoparticles to them.

Drawing up lists of genes associated with the movement of toxins and nanoparticles in cells could help in the design of targeted delivery systems for such agents so they can avoid the lysosome, explains Professor Simpson. “And ultimately, the potential long-term advantage is that you could deliver much lower doses of therapeutic agents and they would be effective.”

Professor Jeremy Simpson was interviewed by freelance journalist Dr Claire O'Connell