Tag Archives: University of Leeds

Better anti-parasitic medicine delivery with chitosan-based nanocapsules

I mage: The common liver fluke which can cause fascioliasis. Credit: Wikimedia creative commons Courtesy: Leeds University

It looks like a pair of lips to me but, according to a December 12, 2018 news item on Nanowerk, this liver fluke heralds a flatworm infection is a serious health problem,

An international team, led by Professor Francisco Goycoolea from the University of Leeds [UK] and Dr Claudio Salomon from the Universidad Nacional de Rosario, Argentina, and in collaboration with colleagues at the University of Münster, Germany, have developed a novel pharmaceutical formulation to administer triclabendazole – an anti-parasitic drug used to treat a type of flatworm infection – in billions of tiny capsules.

The World Health Organisation estimates that 2.4 million people are infected with fascioliasis, the disease caused by flatworms and treated with triclabendazole.

A December 12, 2018 University of Leeds  press release (also on EurekAlert), which originated the news item,

Anti-parasitic drugs do not become effective until they dissolve and are absorbed. Traditionally, these medicines are highly insoluble and this limits their therapeutic effect.
In a bid to overcome this limitation and accomplish the new formulation, the team used “soft” nanotechnology and nanomedicine approaches, which utilises the self-assembly properties of organic nanostructures and uses techniques in which components, such as polymers and surfactants in solution, play key roles.

Their formulation produces capsules that are less than one micron in size – the diameter of a human hair is roughly 75 microns. These tiny capsules are loaded with triclabendazole and then bundled together to deliver the required dose.

The team used chitosan, a naturally-occurring sugar polymer found in the exoskeleton of shellfish and the cell walls of certain fungi, to coat the oil-core of capsules and bind the drug together, while stabilising the capsule and helping to preserve it.
In its nanocapsule form, the drug would be 100 times more soluble than its current tablet form.

Professor Goycoolea, from the School of Food Science and Nutrition at Leeds, said: “Solubility is critical challenge for effective anti-parasite medicine. We looked to tackle this problem at the particle level. Triclabendazole taken as a dose made up of billions of tiny capsules would mean the medicine would be more efficiently and quickly absorbed

“Through the use of nanocapsules and nanoemulsions, drug efficiency can be enhanced and new solutions can be considered for the best ways to target medicine delivery.”
Dr Salomon said: “To date, this is the first report on triclabendazole nanoencapsulation and we believe this type of formulation could be applied to other anti-parasitic drugs as well. But more research is needed to ensure this new pharmaceutical formulation of the drug does not diminish the anti-parasitic effect. Our ongoing research is working to answer this very question.”

Although there have been cases of fascioliasis in more than 70 countries worldwide, with increasing reports from Europe and the Americas, it is considered a neglected disease, as it does not receive much attention and often goes untreated.
Symptoms of the disease when it reaches the chronic phase include intermittent pain, jaundice and anaemia. Patients can also experience hardening of the liver in the case of long-term inflammation.

Because of the highly insoluble nature of anti-parasitic drugs, they need to be administered in very high dosages to ensure enough of the active ingredient is absorbed. This is particularly problematic when treating children for parasites. Tablets needs to be divided into smaller pieces to adjust the dosage and make swallowing easier, but this can cause side effects due to incorrect dosage.

The team’s technique to formulate triclabendazole into nanocapsules, published today [Dec. 12, 2018] in the journal PLOS ONE, would also allow for lower doses to be administered. s

Here’s a link to and a citation for the paper,

Chitosan-based nanodelivery systems applied to the development of novel triclabendazole formulations by Daniel Real, Stefan Hoffmann, Darío Leonardi, Claudio Salomon, Francisco M. Goycoolea. PLOS DOI https://doi.org/10.1371/journal.pone.0207625 Published: December 12, 2018

This paper is open access. BTW, I loved the title for the press release (Helping the anti-parasitic medicine go down) for its reference to the song, A spoonful of sugar helps the medicine go down, in the 1964 film musical, Mary Poppins, and the shout out for the sort of sequel, Mary Poppins Returns, released on Dec. 19, 2018.

Mimicking nature’s ‘anti-freeze’

Some frogs can survive being frozen for weeks and that’s the property scientists at the University of Leeds (UK) are trying to mimic according to a May 19, 2016 news item on Nanowerk (Note: A link has been removed),

The new research, published today [May 18, 2016] in the print edition of the Journal of Physical Chemistry B (“Low-Density Water Structure Observed in a Nanosegregated Cryoprotectant Solution at Low Temperatures from 285 to 238 K”), reveals how glycerol prevents ice crystals from forming in water as the solution is cooled to -35°C, with important implications for improving cryoprotectants used in fertility treatments and food storage.

A May 19, 2016 University of Leeds press release (also on EurekAlert), which originated the news item, provides more detail (Note: A link has been removed),

Dr Lorna Dougan from the University’s School of Physics and Astronomy, who leads the research group, said: “The experiments provide more insight into the fundamental properties of water. It raises questions about what cryoprotectants are doing in living organisms and could help us take steps to understanding how these organisms survive.

“If we understand what glycerol is doing we might be able to fine-tune some of these cryoprotectants that are used to find more effective combinations.”

Cryoprotectant molecules, including glycerol, play an important role in protecting cells and tissues from harmful ice crystals when they are cooled to sub-zero temperatures during freeze storage. Experts have adopted the use of cryoprotectants in fertility treatments and food storage, but not as effectively as in nature.

It is the ability of organisms that can survive in extreme cold environments – known as ‘psychrophiles’ – that inspired the team of physicists to unpick the biological rules that allow their survival.

In winter months, for example, the Eastern Wood frog in North America survives being frozen to temperatures as low as -8°C for weeks, and then in spring thaws out and continues to live perfectly healthily.

To understand how reptiles like the Eastern Wood frog can freeze and thaw, the team used a Science and Technology Facilities Council (STFC) instrument called SANDALS that was purpose-built for investigating the structure of liquids and amorphous materials.

They wanted to answer the fundamental question of how cryoprotectants alter the structure of water at low temperatures, as it is the water structure that is so important in leading to potential ice damage.

The SANDALS instrument allowed the team to see, at the molecular level, that the water and glycerol segregated into clusters. When they looked in more detail, they found the water looked similar to a low density form of itself, showing all the signs it was about to freeze but then it did not. Instead, the glycerol molecules encapsulated the water, preventing the formation of an icy network.

The team will now use these results as a platform for discovering the next generation of cryoprotectants.

Here’s a link to and a citation for the paper,

Low-Density Water Structure Observed in a Nanosegregated Cryoprotectant Solution at Low Temperatures from 285 to 238 K by J. J. Towey, A. K. Soper, and L. Dougan. J. Phys. Chem. B, 2016, 120 (19), pp 4439–4448 DOI: 10.1021/acs.jpcb.6b01185 Publication Date (Web): March 18, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

I did search for images of Eastern Wood Frogs but they have to be paid for. These frogs must be a very much in demand as I’ve haven’t encountered this before. You can usually find what you want on Wikipedia or on a frog enthusiast site. It’s not an Eastern one but here’s a Wood Frog (from Wikipedia),

Lithobates sylvaticus (Woodfrog) Date: 3 July 2011, 19:31 Author:Brian Gratwicke This file is licensed under the Creative Commons Attribution 2.0 Generic license.

Lithobates sylvaticus (Woodfrog)
Date: 3 July 2011, 19:31
Author: Brian Gratwicke
This file is licensed under the Creative Commons Attribution 2.0 Generic license.

The sound of moving data

In fact, scientists from the University of Sheffield (UK) and the University of Leeds (UK) have found a way to move data easily and quickly by using sound waves. From a Nov. 3, 2015 news item on ScienceDaily,

Nothing is more frustrating that watching that circle spinning in the centre of your screen, while you wait for your computer to load a programme or access the data you need. Now a team from the Universities of Sheffield and Leeds may have found the answer to faster computing: sound.

The research — published in Applied Physics Letters — has shown that certain types of sound waves can move data quickly, using minimal power.

A Nov. 3, 2015 University of Sheffield news release on EurekAlert, which originated the news item, explains some of the issues with data and memory before briefly describing how sound waves could provide a solution,

The world’s 2.7 zettabytes (2.7 followed by 21 zeros) of data are mostly held on hard disk drives: magnetic disks that work like miniaturised record players, with the data read by sensors that scan over the disk’s surface as it spins. But because this involves moving parts, there are limits on how fast it can operate.

For computers to run faster, we need to create “solid-state” drives that eliminate the need for moving parts – essentially making the data move, not the device on which it’s stored. Flash-based solid-state disk drives have achieved this, and store information electrically rather than magnetically. However, while they operate much faster than normal hard disks, they last much less time before becoming unreliable, are much more expensive and still run much slower than other parts of a modern computer – limiting total speed.

Creating a magnetic solid-state drive could overcome all of these problems. One solution being developed is ‘racetrack memory’, which uses tiny magnetic wires, each one hundreds of times thinner than a human hair, down which magnetic “bits” of data run like racing cars around a track. Existing research into racetrack memory has focused on using magnetic fields or electric currents to move the data bits down the wires. However, both these options create heat and reduce power efficiency, which will limit battery life, increase energy bills and CO2 emissions.

Dr Tom Hayward from the University of Sheffield and Professor John Cunningham from the University of Leeds have together come up with a completely new solution: passing sound waves across the surface on which the wires are fixed. They also found that the direction of data flow depends on the pitch of the sound generated – in effect they “sang” to the data to move it.

The sound used is in the form of surface acoustic waves – the same as the most destructive wave that can emanate from an earthquake. Although already harnessed for use in electronics and other areas of engineering, this is the first time surface acoustic waves have been applied to a data storage system.

Dr Hayward, from Sheffield’s Faculty of Engineering, said: “The key advantage of surface acoustic waves in this application is their ability to travel up to several centimetres without decaying, which at the nano-scale is a huge distance. Because of this, we think a single sound wave could be used to “sing” to large numbers of nanowires simultaneously, enabling us to move a lot of data using very little power. We’re now aiming to create prototype devices in which this concept can be fully tested.”

Here’s a link to and a citation for the paper,

A sound idea: Manipulating domain walls in magnetic nanowires using surface acoustic waves by J. Dean, M. T. Bryan, J. D. Cooper, A. Virbule, J. E. Cunningham, and T. J. Hayward. Appl. Phys. Lett. 107, 142405 (2015); http://dx.doi.org/10.1063/1.4932057

This is an open access paper.

Dexter Johnson in a Nov. 5, 2015 posting on his Nanoclast blog (on the IEEE [Institute of Electrical and Electronics Engineers] website) provides a few additional details about the work such as a brief mention of IBM’s work developing racetrack memory, also known as, a non-volatile memory device.

Watching motor proteins at work

Researchers in the UK and in Japan have described these motor proteins as ‘swinging on monkey bars’,

A Sept. 14, 2015 news item on Nanowerk provides more information about the motor protein observations,

These proteins are vital to complex life, forming the transport infrastructure that allows different parts of cells to specialise in particular functions. Until now, the way they move has never been directly observed.

Researchers at the University of Leeds and in Japan used electron microscopes to capture images of the largest type of motor protein, called dynein, during the act of stepping along its molecular track.

A Sept 14, 2015 Leeds University press release, (also on EurekAlert*) which originated the news item, expands on the theme with what amounts to a transcript of sorts for the video (Note: Links have been removed),

Dr Stan Burgess, at the University of Leeds’ School of Molecular and Cellular Biology, who led the research team, said: “Dynein has two identical motors tied together and it moves along a molecular track called a microtubule. It drives itself along the track by alternately grabbing hold of a binding site, executing a power stroke, then letting go, like a person swinging on monkey bars.

“Previously, dynein movement had only been tracked by attaching fluorescent molecules to the proteins and observing the fluorescence using very powerful light microscopes. It was a bit like tracking vehicles from space with GPS. It told us where they were, their speed and for how long they ran, stopped and so on, but we couldn’t see the molecules in action themselves. These are the first images of these vital processes.”

An understanding of motor proteins is important to medical research because of their fundamental role in complex cellular life. Many viruses hijack motor proteins to hitch a ride to the nucleus for replication. Cell division is driven by motor proteins and so insights into their mechanics could be relevant to cancer research. Some motor neurone diseases are also associated with disruption of motor protein traffic.

The team at Leeds, working within the world-leading Astbury Centre for Structural Molecular Biology, combined purified microtubules with purified dynein motors and added the chemical fuel ATP (adenosine triphosphate) to power the motor.

Dr Hiroshi Imai, now Assistant Professor in the Department of Biological Sciences at Chuo University, Japan, carried out the experiments while working at the University of Leeds.

He explained: “We set the dyneins running along their tracks and then we froze them in ‘mid-stride’ by cooling them at about a million degrees a second, fast enough to prevent the water from forming ice crystals as it solidified. Then using a cryo-electron microscope we took many thousands of images of the motors caught during the act of stepping. By combining many images of individual motors, we were able to sharpen up our picture of the dynein and build up a dynamic idea of how it moved. It is a bit like figuring out how to swing along monkey bars by studying photographs of many people swinging on them.”

Dr Burgess said: “Our most striking discovery was the existence of a hinge between the long, thin stalk and the ‘grappling hook’, like the wrist between a human arm and hand. This allows a lot of variation in the angle of attachment of the motor to its track.

“Each of the two arms of a dynein motor protein is about 25 nanometres (0.000025 millimetre) long, while the binding sites it attaches to are only 8 nanometres apart. That means dynein can reach not only the next rung but the one after that and the one after that and appears to give it flexibility in how it moves along the ‘track’.”

Dynein is not only the biggest but also the most versatile of the motor proteins in living cells and, like all motor proteins, is vital to life. Motor proteins transport cargoes and hold many cellular components in position within the cell. For instance, dynein is responsible for carrying messages from the tips of active nerve cells back to the nucleus and these messages keep the nerve cells alive.

Co-author Peter Knight, Professor of Molecular Contractility in the University of Leeds’ School of Molecular and Cellular Biology, said: “If a cell is like a city, these are like the truckers on its road and rail networks. If you didn’t have a transport system, you couldn’t have specialised regions. Every part of the cell would be doing the same thing and that would mean you could not have complex life.”

“Dynein is the multi-purpose vehicle of cellular transport. Other motor proteins, called kinesins and myosins, are much smaller and have specific functions, but dynein can turn its hand to a lot of different of functions,” Professor Knight said.

For instance, in the motor neurone connecting the central nervous system to the big toe—which is a single cell a metre long— dynein provides the transport from the toe back to the nucleus. Another vital role is in the movement of cells.

Dr Burgess said: “During brain development, neurones must crawl into their correct position and dynein molecules in this instance grab hold of the nucleus and pull it along with the moving mass of the cell. If they didn’t, the nucleus would be left behind and the cytoplasm would crawl away.”

The study involved researchers from the University of Leeds and Japan’s Waseda and Osaka universities, as well as the Quantitative Biology Center at Japan’s Riken research institute and the Japan Science and Technology Agency (JST). The research was funded by the Human Frontiers Science Program and the Biotechnology and Biological Sciences Research Council (BBSRC).

Here’s a link to and a citation for the paper,

Direct observation shows superposition and large scale flexibility within cytoplasmic dynein motors moving along microtubules by Hiroshi Imai, Tomohiro Shima, Kazuo Sutoh, Matthew L. Walker, Peter J. Knight, Takahide Kon, & Stan A. Burgess. Nature Communications 6, Article number: 8179  doi:10.1038/ncomms9179 Published 14 September 2015

This paper is open access.

*The EurekAlert link added Sept. 15, 2015 at 1200 hours PST.

Gold nanotubes could be used in cancer therapies

Where nanotubes are concerned I don’t often see mention of any type other than ‘carbon’ nanotubes so, this Feb. 12, 2015 nanomedicine news item on ScienceDaily featuring ‘gold’ nanotubes caught my attention,

Scientists have shown that gold nanotubes have many applications in fighting cancer: internal nanoprobes for high-resolution imaging; drug delivery vehicles; and agents for destroying cancer cells.

The study, published today in the journal Advanced Functional Materials, details the first successful demonstration of the biomedical use of gold nanotubes in a mouse model of human cancer.

A Feb. 13, 2015 University of Leeds press release, which originated the news item despite what the publication date suggests, describes the research in more detail (Note: Links have been removed),

Study lead author Dr Sunjie Ye, who is based in both the School of Physics and Astronomy and the Leeds Institute for Biomedical and Clinical Sciences at the University of Leeds, said:  “High recurrence rates of tumours after surgical removal remain a formidable challenge in cancer therapy. Chemo- or radiotherapy is often given following surgery to prevent this, but these treatments cause serious side effects.

Gold nanotubes – that is, gold nanoparticles with tubular structures that resemble tiny drinking straws – have the potential to enhance the efficacy of these conventional treatments by integrating diagnosis and therapy in one single system.”

The researchers say that a new technique to control the length of nanotubes underpins the research. By controlling the length, the researchers were able to produce gold nanotubes with the right dimensions to absorb a type of light called ‘near infrared’.

The study’s corresponding author Professor Steve Evans, from the School of Physics and Astronomy at the University of Leeds, said: “Human tissue is transparent for certain frequencies of light – in the red/infrared region. This is why parts of your hand appear red when a torch is shone through it.

“When the gold nanotubes travel through the body, if light of the right frequency is shone on them they absorb the light. This light energy is converted to heat, rather like the warmth generated by the Sun on skin. Using a pulsed laser beam, we were able to rapidly raise the temperature in the vicinity of the nanotubes so that it was high enough to destroy cancer cells.”

In cell-based studies, by adjusting the brightness of the laser pulse, the researchers say they were able to control whether the gold nanotubes were in cancer-destruction mode, or ready to image tumours.

In order to see the gold nanotubes in the body, the researchers used a new type of  imaging technique called ‘multispectral optoacoustic tomography’ (MSOT) to detect the gold nanotubes in mice, in which gold nanotubes had been injected intravenously. It is the first biomedical application of gold nanotubes within a living organism. It was also shown that gold nanotubes were excreted from the body and therefore are unlikely to cause problems in terms of toxicity, an important consideration when developing nanoparticles for clinical use.

Study co-author Dr James McLaughlan, from the School of Electronic & Electrical Engineering at the University of Leeds, said: “This is the first demonstration of the production, and use for imaging and cancer therapy, of gold nanotubes that strongly absorb light within the ‘optical window’ of biological tissue.

“The nanotubes can be tumour-targeted and have a central ‘hollow’ core that can be loaded with a therapeutic payload. This combination of targeting and localised release of a therapeutic agent could, in this age of personalised medicine, be used to identify and treat cancer with minimal toxicity to patients.”

The use of gold nanotubes in imaging and other biomedical applications is currently progressing through trial stages towards early clinical studies.

Here’s a link to and a citation for the paper,

Engineering Gold Nanotubes with Controlled Length and Near-Infrared Absorption for Theranostic Applications by Sunjie Ye, Gemma Marston, James R. McLaughlan, Daniel O. Sigle, Nicola Ingram, Steven Freear, Jeremy J. Baumberg, Richard J. Bushby, Alexander F. Markham, Kevin Critchley, Patricia Louise Coletta, and Stephen D. Evans. Advanced Functional Materials DOI: 10.1002/adfm.201404358 Article first published online: 12 FEB 2015

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.