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World’s tiniest drug cabinets could be attached to cancerous cells for long-term treatment. 15.01.2014

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World’s tiniest drug cabinets could be attached to cancerous cells for long-term treatment. 15.01.2014

Reservoirs of anti-viral pharmaceuticals could be manufactured to bind specifically to infected tissue such as cancer cells for slow, concentrated delivery of drug treatments, according to new research published in ACS Macro Letters.

The findings, from the University of Copenhagen and the Institut Laue-Langevin (ILL), are the direct result of neutron reflectometry studies at the ILL, the world’s leading neutron source in Grenoble, France. They could provide a way to reduce the dosages and frequency of injections administered to patients undergoing a wide variety of treatments, as well as minimising side effects of over-dosing.


The attachment of reservoirs of therapeutic drugs to cell membranes for slow diffusion and continuous delivery inside the cells is a major aim in drug R&D. A promising candidate for packaging and carrying mixtures of drugs is a group of self-assembled liquid crystalline particles. These particles are composed of fatty molecules – phospholipids - and tree-like macromolecules called dendrimers; they form spontaneously and have the capacity to soak up and carry large quantities of drug molecules for prolonged diffusion. They are also known for their ability to bind to cellular membranes.

The first treatments using such particles are close to being marketed through products incorporating a similar formulation called "cubosomes" (cubic phase nanoparticles), developed and commercialized by Swedish start-up Camurus Ab. Camurus's FluidCrystal® nanoparticles promise months of drug delivery from a single injection, including the possibility of tuning the delivery to intervals of anything from once a day to once a month. However, a key requirement for the optimal application of these formulations is a detailed understanding of how they interact with cellular membranes.

This was the focus of a collaboration between Dr Marité Cárdenas (Copenhagen) and Dr Richard Campbell and Dr Erik Watkins (ILL). In this experiment the team used neutrons to analyse the interaction of the liquid crystalline particles with a model cellular membrane with respect to two parameters:

•    Gravity – to see how the interaction changed if the aggregates attacked the cell membrane from below as opposed to above
•    Electrostatics – to see how the balance between positive and negative charges of the aggregate and membrane affect the interaction

The team used a technique known as neutron reflectometry, whereby beams of neutrons are skimmed off a surface. The reflectivity is measured and used to infer detailed information about the surface, including the thickness, detailed structure and composition of any layers beneath. These experiments were carried out at the ILL in Grenoble on the instrument FIGARO, which offers unique reflection-up vs. reflection-down modes. Using FIGARO the team was able to examine the top and bottom surfaces, alternating the samples on a two-hourly basis during a 30-hour sampling period.

The interaction of the liquid crystalline particles with the membrane was shown to be driven by the charge on the model cell membrane. Subtle changes in the degree of negative charge on the membrane encouraged the tree-like dendrimer molecules to penetrate, allowing the rest of the molecule to bind to the surface, forming an attached reservoir. The sensitivity of the interaction to small changes in charge suggests that simple adjustments to the proportion of charged lipids and macromolecules could optimise this attachment. In the future this characteristic could also provide a mechanism to focus the treatment at cells being targeted, such as those infected by cancer which are thought to be more negatively charged than healthy cells.

In terms of gravitational effects, the analysis also showed that aggregates interacted more strongly with membranes when located above the sample. Similar effects caused by differences in the density and buoyancy of solutions are already being exploited in stomach treatments; the researchers would encourage future studies into how gravitational effects could be used to optimise these interactions for drug delivery.


Quotes

“Cancerous cells have an imbalance that gives them a different molecular composition and very different physical properties compared to normal healthy cells”, explains Dr Cardenas. “Whilst all cells are negative, cancerous cells tend to be more negatively charged than healthy ones due to a different composition of fatty molecules on their surface. This is a property that we believe could be exploited in future research into delivery mechanisms involving the attachment of lamellar liquid crystalline particles. Our next step is to introduce the drug itself into the reservoirs and make sure it can move across the membrane. This work paves the way for future cell tests and clinical trials exploiting our methodology.”

“Of course it’s not new that particles in formulations can sink or float, but such dramatically different specific interactions of these nanocarriers with model membranes of different orientations took us completely by surprise” said Dr Campbell. “Very small sample volumes are often used in biomedical investigations, so the effects of phase separation cannot be seen. Our findings suggest that laboratory researchers may need to re-evaluate the way in which they examine the effectiveness of newly developed formulations to account for strong gravitational effects.”

Dr Watkins further commented: “This study is a perfect illustration of FIGARO’s unique capability to take data from above and below horizontal interfaces in the same experiment. Not only are neutrons uniquely sensitive to the lighter elements found in organic chemistry, but the ability to take all the data at once in situ without disturbing the sample is vital. These biological samples are always changing subtly throughout the analysis, so it's vital that the data be taken as quickly as possible.”





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Note to editors


About ILL – The Institut Laue-Langevin (ILL) is an international research centre based in Grenoble, France. It has led the world in neutron-scattering science and technology for more than 40 years, since experiments began in 1972. ILL operates one of the most intense neutron sources in the world, feeding beams of neutrons to a suite of 40 high-performance instruments that are constantly upgraded. Each year 1,200 researchers from over 40 countries visit ILL to conduct research into condensed matter physics, (green) chemistry, biology, nuclear physics, and materials science. The UK, along with France and Germany is an associate and major funder of the ILL.

Uppsala University is the oldest university in the Nordic countries, with a living cultural environment and fantastic student life. There are 40,000 students here, and they are seen, heard, and noticed everywhere. World-class research and high quality education pursued here benefit society and business on a global level. The University is characterized by diversity and breadth, with international frontline research at nine faculties and limitless educational offerings at undergraduate and master levels. - See more at: www.uu.se/en/about-uu/in-brief/

Uppsala University is the oldest university in the Nordic countries, with a living cultural environment and fantastic student life. There are 40,000 students here, and they are seen, heard, and noticed everywhere. World-class research and high quality education pursued here benefit society and business on a global level. The University is characterized by diversity and breadth, with international frontline research at nine faculties and limitless educational offerings at undergraduate and master levels. - See more at: www.uu.se/en/about-uu/in-brief/