Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

Abstract

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, like adenosine, are inefficient upon systemic administration because of their fast metabolisation and rapid clearance from the bloodstream. Here, we show that the conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allow a prolonged circulation of this nucleoside, to provide neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed 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. This paper shows, for the first time, that a hydrophilic and rapidly metabolised molecule like adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

“…In this study, we show that synthetic cabazitaxel prodrugs tethered with PUFAs are able to recapitulate self-assembly behavior in aqueous solutions independent of excipients. PUFAs, which are structurally analogous to the squalene moiety that was developed for drug conjugation by Couvreur and colleagues (28,44), exhibit several unique features as follows: (i) they have possible p-p stacking between prodrug molecules that renders nanoassemblies sufficiently stable in vivo; (ii) they are commercially available and inexpensive; and (iii) these entities play an essential role in biological functions and are also abundant in the human body, thereby obviating concerns over excipient-associated side effects (45). These features promise PUFAs as useful skeletons for the generation of oncology drugs.…”

Cerebral microvascular pericytes and neurogliovascular signaling in health and disease

“…Restoration of microcirculatory patency with agents inhibiting radical formation administered during recanalization was correlated with the size of tissue surviving, suggesting that microcirculatory obstructions negatively impact recovery after recanalization (Yemisci et al, 2009). More recently, sustained release of adenosine to circulation from nano-assemblies has been shown to reduce ischemiainduced erythrocyte entrapments and improve microcirculatory reflow by relaxing contracted pericytes after 2 hours of MCA occlusion (Gaudin et al, 2014) (Fig. 8).…”

Influence of the nanoprecipitation conditions on the supramolecular structure of squalenoyled nanoparticles

“…SQAc-Ad NPs revealed impressive neuroprotective activity in both a stroke (cerebral ischemia) and spinal cord injury models [24]. Indeed, the intravenous administration of NPs reduced the infarct volume in experimental cerebral ischemia in mice and dramatically improved the functional recovery of spinal cord injured rats with impressive improvement of animal neurological scores.…”