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06/24/2021

01/20/2014

Reservoirs of anti-viral pharmaceuticals could be attached to cancerous cells for long-term treatment

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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.

    » Original publication

    Source: Institut Laue-Langevin (ILL)