Abstract
Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. Nanoparticles hold tremendous promise to overcome the pharmacokinetic challenges and off-target adverse effects. However, an inhibitory effect of nanoparticles by themselves on metastasis has not been explored. In this study, we developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Tf@pSiNP were colloidally stable, biocompatible, and their uptake into GBM cells was enhanced by receptor-mediated internalisation. The migration of Tf@pSiNP-exposed cells across the confined microchannels was suppressed, but unconfined migration was unaffected. The pSiNP-induced destabilisation of focal adhesions at the leading front may partially explain the migration inhibition. More corroborating evidence suggests that pSiNP uptake reduced the plasticity of GBM cells in reducing cell volume, an effect that proved crucial in facilitating migration across the tight confined tracts. We believe that the inhibitory effect of Tf@pSiNP on cell migration, together with the drug-delivery capability of pSiNP, could potentially offer a disruptive strategy to treat GBM.
Highlights
Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers
The conjugation of Tf onto Porous silicon nanoparticle (pSiNP) was performed as described in Fig. 1A, and the hydrodynamic particle size distribution and zeta potential were characterised by dynamic light scattering (DLS) with zeta-potential analyser
DLS results, measured an average size of Tf@pSiNP of 182 ± 0.8 nm, and the particle size distribution was narrow as indicated by a polydispersity index of 0.1 (Fig. 1B)
Summary
Mortality of glioblastoma multiforme (GBM) has not improved over the last two decades despite medical breakthroughs in the treatment of other types of cancers. We developed transferrin-conjugated porous silicon nanoparticles (Tf@pSiNP) and studied their effect on inhibiting GBM migration by means of a microfluidic-based migration chip. This platform, designed to mimic the tight extracellular migration tracts in brain parenchyma, allowed high-content time-resolved imaging of cell migration. Deriving therapeutic counter measures against aforementioned infiltrative migration mechanisms employed by a cancer cell (such as the use of small molecules[11], peptides[12], RNA interference13) has been an obvious approach to intervene cancer progression[14] Despite those discoveries, the pharmacokinetic challenges such as rapid degradation, clearance of those small molecules, and off-target adverse effects are still problematic in clinical translation. Studies on the potential of NP treatments in attenuating GBM invasion and migration are absent, despite the hallmark of GBM being their infiltrative phenotype
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