43 research outputs found
Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF)
AbstractMultiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of âŒ120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination.Impact statementNanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS
Magnetically Coated Bioabsorbable Stents for Renormalization of Arterial Vessel Walls after Stent Implantation
The
insertion of a stent in diseased arteries is a common endovascular
procedure that can be compromised by the development of short- and
long-term inflammatory responses leading to restenosis and thrombosis,
respectively. While treatment with drugs, either systemic or localized,
has decreased the incidence of restenosis and thrombosis these complications
persist and are associated with a high mortality in those that present
with stent thrombosis. We reasoned that if stents could be made to
undergo accelerated endothelialization in the deployed region, then
such an approach would further decrease the occurrence of stent thrombosis
and restenosis thereby improving clinical outcomes. Toward that objective,
the first step necessitated efficient capture of progenitor stem cells,
which eventually would become the new endothelium. To achieve this
objective, we engineered intrinsic ferromagnetism within nonmagnetizable,
biodegradable magnesium (Mg) bare metal stents. Mg stents were coated
with biodegradable polylactide (PLA) polymer embedding magnetizable
ironâplatinum (FePt) alloy nanoparticles, nanomagnetic particles, <sup>n</sup>Mags, which increased the surface area and hence magnetization
of the stent. <sup>n</sup>Mags uniformly distributed on stents enabled
capture, under flow, up to 50 mL/min, of systemically injected iron-oxide-labeled
(IO-labeled) progenitor stem cells. Critical parameters enhancing
capture efficiency were optimized, and we demonstrated the generality
of the approach by showing that <sup>n</sup>Mag-coated stents can
capture different cell types. Our work is a potential paradigm shift
in engineering stents because implants are rendered as tissue in the
body, and this ânatural stealthinessâ reduces or eliminates
issues associated with pro-inflammatory immune responses postimplantation