SQAd nanoparticles could help speed up stroke recovery

Nanoparticles made from the fatty biomolecule squalene and the nucleoside adenosine could help protect neurons following a stroke or spinal-cord injury at least in mice according to new experiments by researchers in France and Turkey. The finding proves that such simple treatments might be better than conventional pharmaceutical therapies for treating severe neurological trauma.

It is difficult to treat brain diseases using drugs that act on the central nervous system. This is because most drugs rapidly break down (or metabolize) in the bloodstream and diffuse rather poorly through the blood-brain barrier (BBB) and blood-spinal-cord barrier (BSCB). These drugs can often be toxic too, with a number of unpleasant side effects. Brain and cerebral diseases are also highly complex often involving multiple interactions between the blood vessels of the brain and its neurons and glial cells.

Nanotechnology could come into its own here because it could help improve drug delivery to the brain.

New experiments by Patrick Couvreur of the University Paris-Sud and colleagues have shown that nanoparticles made of adenosine combined with squalene appear to protect neurons following a stroke (cerebral ischemia) or spinal-cord injury. Adenosine is a good vasodilator but it cannot be used on its own for such therapies because it rapidly breaks down in the bloodstream and cannot pass the BBB or BCSB. When squalenylacetic acid is covalently linked onto the amino group of adenosine, however, and made into an amphiphilic prodrug that spontaneously forms into nanoparticles around 120nm in size, these problems seem to disappear. In fact, the prodrug squalenoyl adenosine (SQAd) appears to protect the adenosine from rapidly metabolizing in the body, explains Couvreur.

Such squalenoylation technology, as it is known, is not new and has already been tested, with success, to treat cancer before now. But, this is the first time that it has been used to deliver therapeutics to treat central nervous system injuries.

The researchers prepared their nanoassemblies by nanoprecipitating an alcoholic solution of SQAd in a 5% aqueous dextrose solution without any added surfactant. The absence of a surfactant also makes the ensemble much less toxic. And, since adenosine is not physically encapsulated but only covalently linked to the lipid nanocarrier squalenylacetic acid, it is possible to load a large amount of drug into it.

To test out their nanoparticles, Couvreur and colleagues injected this suspension into mice that had suffered from strokes or rats with spinal-cord injuries. The animals appeared to recover the use of their hind limbs, in the case of spinal-cord injuries, much more quickly than those (control groups) that had received only dextrose, free adenosine and unconjugated squalenoyl (SQ) nanoassemblies. These animals recovered from their strokes much more quickly too (in as little as six hours, in fact) as confirmed by florescence imaging studies of blood vessel microcapillaries that unclogged or dilated.

And that is not all: Couvreurs team also found that the SQAd nanoparticle assemblies were non-toxic. Since adenosine is a neuromodulator and involved in numerous neurological processes, it should cause side effects, such as loss of appetite or acute drowsiness. To shed more light on such potential dangers, the researchers monitored how much food the mice ate following treatment, as well as the animals body weight and their sleep cycles. They found that intravenously administering the SQAd nanoassemblies (at levels of up to 15mg per kg of the rodents body weight) did not affect the animals behaviour in any way compared with the control groups.

Although we do need to undertake further studies to more precisely describe the exact therapeutic mechanism and determine how dose and the frequency at which we administer SQAd nanoassemblies may affect clinical outcomes, our study points towards new perspectives for treating severe neurological diseases where tissue ischemia and/or neurological trauma are involved, Couvreur told nanotechweb.org.

The team, which includes researchers from Hacettepe University in Ankara, reports its work in Nature Nanotechnology doi:10.1038/nnano.2014.274.

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SQAd nanoparticles could help speed up stroke recovery