Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

Developers

Alice Gaudin, Müge Yemisci, Hakan Eroglu, Turgay Dalkara, Patrick Couvreur etc.

Description of the technology

It is new technology, which allows using adenosine, currently unusable as a neuroprotective drug following intravenous injection. There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream.

Bioconjugation of adenosine to the natural and biocompatible lipid squalene to form an amphiphilic prodrug led to the spontaneous formation of nanoassemblies (nanoparticles) with a size of ca. 120 nm. This transformation of adenosine provides: (1) an efficient protection of adenosine from rapid metabolisation, (3) the induction of a dramatic neuroprotective effect in both an ischaemia-reperfusion model in mice and a spinal cord injury model in rats, likely due to (3) a prolonged drug interaction with the neurovascular unit, (4) without triggering any side-effects nor inducing systemic toxicity.

Neuroprotective effect of new formulation of adenosine was tested in experiment, which showed that it really provided neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies had a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. The results of application of this method demonstrated, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine might become pharmacologically efficient owing to a single conjugation with the lipid squalene. The «squalenoylation» technology has already been applied to the intravenous administration of anticancer and antiretroviral compounds. However, in this method it has been applied, for the first time, for the delivery of therapeutic amounts of drugs to treat CNS injuries.

Practical application

This technology showed for the first time that the linkage of adenosine to squalene and the subsequent construction as nanoassemblies allow the efficient administration of this molecule with significant pharmacological activity in a brain ischaemia and a spinal cord injury models. The demonstrated plasma reservoir effect of SQAd NAs allowed improvement of microcirculation leading to a secondary parenchyma neuroprotection. Although further studies are needed to more precisely describe the exact therapeutic mechanism and to determine how dosage, administration frequency and timing of treatment with SQAd NAs may affect the clinical outcome, this study opens a new exciting perspective for the treatment of severe neurological diseases where tissue ischaemia and/or trauma are involved.
The method can be, in prospect, applied for therapy of age-associated diseases and conditions, such as age-associated disorders of cerebral circulation, etc.

Laboratories

• Institut Galien Paris-Sud UMR CNRS 8612, Faculty of Pharmacy, University of Paris-Sud XI, Châtenay-Malabry (France)
• Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara (Turkey)
• Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara (Turkey)
• Department of Neurosurgery, Ankara Ataturk Research & Education Hospital, Bilkent, Ankara (Turkey)

Links

Publications

• Gaudin, A et al. «Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury." 9 Nature Nanotechnology, (2014): 1054–1062.
• Saucier-Sawyer JK, et al. «Distribution of polymer nanoparticles by convection-enhanced delivery to brain tumors." 232 J Control Release. (2016): 103−112.
• Gaudin, A et al. «Pharmacokinetics, biodistribution and metabolism of squalenoyl adenosine nanoparticles in mice using dual radio-labeling and radio-HPLC analysis." 212 J Control Release. (2015): 50−58.