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Anthrax toxin: a new tool in the fight against cancer?

Target Station 1 Experimental Hall at the ISIS Neutron and Muon Source, where the neutron experiments took place on instrument, LOQ.
(Credit: STFC)

26th January 2016 – Anthrax, the lethal disease, could turn out to be an unexpected tool in the fight against cancer. Famed for being deadly rather than known as a treatment, the bacterium behind anthrax has been shown by scientists to be a possible solution for delivering drugs for a specific form of gene therapy.

This novel approach towards treating disease could also have anti-viral and food security applications.

A team led by Dr Simon Richardson at the University of Greenwich has shown that by disarming the ‘warhead’ within anthrax, the toxin can be converted into a positive tool for delivering ‘heavy’ drugs, or those with a large mass, to where they are most needed within the cell.

“This is the first time a disarmed toxin has been used to deliver gene-modulating drugs directly to a specific compartment within the cell. We’ve achieved this without the use of so called helper molecules, such as large positively charged molecules like poly(L-lysine). This is important as while these positively charged molecules, known as polycations, can condense DNA and protect it from attack by enzymes before it reaches the target, they are also known to be toxic, break cell membranes and are sent quickly to the liver to be removed from the body. In this study we demonstrate that using disarmed toxins without a polycation is effective, at a cellular level," said Dr Simon Richardson, team leader from the University of Greenwich.

During the development of this technology, scientists used STFC’s ISIS Neutron and Muon Source to visualise the system they’d built at the molecular level. Neutron measurements enabled the scientists to see that the drug delivery molecules they had designed were behaving as they had predicted.

This new breakthrough builds upon years of research that has shown that synthetic, man-made materials (that have many well-known limitations) are not the only tools that can be used to deliver gene therapy drugs. The gene therapy drug that this technology has been developed in relation to is known as antisense (or siRNA) therapy, which effectively turns off the expression of a gene causing problems.

The research has been published in the Journal of Controlled Release.

Anthrax is an acute disease caused by a bacterium that spreads via spores, which can become fatal when activated. Its ability to spread through the body so ‘effectively’ makes it attractive to scientists as a potential tool for drug delivery. By exploiting anthrax toxin’s natural ability to navigate cells’ defences, the toxin components can be used to access specific compartments within a cell.

Using genetic engineering, the team has shown that the anthrax toxin’s ‘warhead’ can be replaced with a gene therapy drug. The toxin’s ‘rocket motor’ is left in place and can be used to transport the drug to the inside (the cytosol) of the cell, preventing it from being digested in the cell’s stomach (or endolysosome). Rather than making a hole in the cell to get inside, which is harmful, this delivery system uses anthrax’s natural ability to get to specific compartments within a cell through an “airlock” like system, leaving the cells membranes unharmed.

Lead scientist of the neutron study, Dr Paul Dyer from the University of Greenwich, said: "Understanding the nature of toxin pore biology, in particular how proteins transit through the pore, provides insights into novel drug delivery strategies and therapeutics to prevent Anthrax intoxication in animal and humans. We are currently using neutron reflectometry and scattering to evaluate this process in nanodiscs containing the anthrax pore.”

Antisense therapy, a type of gene therapy, is being considered as one of the potential options for treating cancer. Without the delivery system the therapy looks promising but lacks the ability to effectively reach the correct compartment inside the cell. Consequently, scientists Richardson and Dyer are investigating whether the modified anthrax toxin will provide a solution; giving the drug the extra boost they need to get to the right part of the cell to produce an effect.

To test the delivery system, experiments were done on cancerous human cells (both HeLa (cervical cancer) and THP-1 (leukemia) cells) that were grown in the laboratory at the University of Greenwich.

Scientists were able to deliver these drugs to their end destination with high efficiency and low toxicity, showing that their proposed method is effective thus far.

In this novel approach, team leader Dr Simon Richardson and his laboratory members from the University of Greenwich looked to nature to see how other organisms’ own delivery systems evolved.

“Bacteria and plants produce toxins that access the same part of the cell that these new drugs need to reach, but rather than delivering a therapeutic, they deliver a warhead. We have replaced the warhead with a therapeutic. To this end, we’re stepping away from traditional, non-viral delivery technologies and rather than using synthetic polymers or lipids we are using protein architecture that has evolved to do the job we need it to do.” said Dr Richardson.

Now that the team have demonstrated that anthrax can be used to deliver the gene therapy drug to the target cell, their focus turns to trying to find out exactly how the drug gets into the cell and if this system can be used in a more complex environment that is more like a patient than cells growing in a dish.

Dr Paul Dyer, first author of the Journal of Controlled Release paper, will return to the ISIS Neutron and Muon Source to lead further neutron experiments. During this time he hopes to see how the ‘gate keeper’, a doughnut-shaped protein which lodges in the cell’s defence, opens the gate for the drug to pass through into the cell. Results from this project may not only impact on the use of gene therapies in the fight against cancer, but may also apply to food security and preventing the release of anthrax both accidentally and deliberately.

Dr John Webster, Group Leader of the Large Scale Structures Group at the ISIS Neutron and Muon Source believes that “Neutron Scattering and Muon Spectroscopy can provide a unique window into the way complex molecules organise themselves. The results here are a good example of where this capability is especially useful when it comes to probing the mechanisms of biological transport such as drug delivery. We look forward to seeing how this work unfolds in the future.”

Notes to editors

Contact

Emily Mobley
Media Officer
STFC
01235 445398 / 07590 443056

The results were published in the printed edition of Journal of Controlled Release on December 28th as an open access paper. The paper has also been reported in the Atlas of Science.

Dr Richardson and Dr Dyer both own shares in Intracellular Delivery Solutions (IDS) Ltd., a company set up to further develop this technology. Dr Richardson also serves as CSO at IDS Ltd.

ISIS

ISIS is a world-leading centre for research in the physical and life sciences at the STFC Rutherford Appleton Laboratory near Oxford in the United Kingdom. Our suite of neutron and muon instruments gives unique insights into the properties of materials on the atomic scale. We support a national and international community of more than 3000 scientists for research into subjects ranging from clean energy and the environment, pharmaceuticals and health care, through to nanotechnology and materials engineering, catalysis and polymers, and on to fundamental studies of materials.

We use the technique of neutron scattering. Neutrons tell us where atoms are and how they are moving. By studying how materials work at the atomic level, we can better understand their every-day properties – and so make new materials tailor-made for particular uses. ISIS also produces muons for use in a similar way, providing additional information on how materials work at the atomic scale.

ISIS Website

University of Greenwich

Dr Simon Richardson, team leader from the University of Greenwich

Dr Paul Dyer, first author of the paper, University of Greenwich

Last updated: 30 April 2018

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