Effectiveness of porous silicon nanoparticle treatment at inhibiting the migration of a heterogeneous glioma cell population

Background: Approximately 80% of brain tumours are gliomas. Despite treatment, patient mortality remains high due to local metastasis and relapse. It has been shown that transferrin-functionalised porous silicon nanoparticles (Tf@pSiNPs) can inhibit the migration of U87 glioma cells. However, the underlying mechanisms and the effect of glioma cell heterogeneity, which is a hallmark of the disease, on the efficacy of Tf@pSiNPs remains to be addressed. Results: Here, we observed that Tf@pSiNPs inhibited heterogeneous patient-derived glioma cells’ (WK1) migration across small perforations (3 μm) by approximately 30%. A phenotypical characterisation of the migrated subpopulations revealed that the majority of them were nestin and fibroblast growth factor receptor 1 positive, an indication of their cancer stem cell origin. The treatment did not inhibit cell migration across large perforations (8 μm), nor cytoskeleton formation. This is in agreement with our previous observations that cellular-volume regulation is a mediator of Tf@pSiNPs’ cell migration inhibition. Since aquaporin 9 (AQP9) is closely linked to cellular-volume regulation, and is highly expressed in glioma, the effect of AQP9 expression on WK1 migration was investigated. We showed that WK1 migration is correlated to the differential expression patterns of AQP9. However, AQP9-silencing did not affect WK1 cell migration across perforations, nor the efficacy of cell migration inhibition mediated by Tf@pSiNPs, suggesting that AQP9 is not a mediator of the inhibition. Conclusion: This in vitro investigation highlights the unique therapeutic potentials of Tf@pSiNPs against glioma cell migration and indicates further optimisations that are required to maximise its therapeutic efficacies. Graphic Abstract: [Figure not available: see fulltext.

Synaptic and Fast Switching Memristance in Porous Silicon-Based Structures

Memristors are two terminal electronic components whose conductance depends on the amount of charge that has flown across them over time. This dependence can be gradual, such as in synaptic memristors, or abrupt, as in resistive switching memristors. Either of these memory effects are very promising for the development of a whole new generation of electronic devices. For the successful implementation of practical memristors, however, the development of low cost industry compatible memristive materials is required. Here the memristive properties of differently processed porous silicon structures are presented, which are suitable for different applications. Electrical characterization and SPICE simulations show that laser-carbonized porous silicon shows a strong synaptic memristive behavior influenced by defect diffusion, while wet-oxidized porous silicon has strong resistance switching properties, with switching ratios over 8000. Results show that practical memristors of either type can be achieved with porous silicon whose memristive properties can be adjusted by the proper material processing. Thus, porous silicon may play an important role for the successful realization of practical memristorics with cost-effective materials and processes

Polydopamine Nanoparticles Prepared Using Redox-Active Transition Metals

Autoxidation of dopamine to polydopamine by dissolved oxygen is a slow process that requires highly alkaline conditions. Polydopamine can be formed rapidly also in mildly acidic and neutral solutions by using redox-active transition-metal ions. We present a comparative study of polydopamine nanoparticles formed by autoxidation and aerobic or anaerobic oxidation in the presence of Ce(IV), Fe(III), Cu(II), and Mn(VII). The UV-vis spectra of the purified nanoparticles are similar, and dopaminechrome is an early intermediate species. At low pH, Cu(II) requires the presence of oxygen and chloride ions to produce polydopamine at a reasonable rate. The changes in dispersibility and surface charge take place at around pH 4, which indicates the presence of ionizable groups, especially carboxylic acids, on their surface. X-ray photoelectron spectroscopy shows the presence of three different classes of carbons, and the carbonyl/carboxylate carbons amount to 5-15 atom %. The N 1s spectra show the presence of protonated free amino groups, suggesting that these groups may interact with the pi-electrons of the intact aromatic dihydroxyindole moieties, especially in the metal-induced samples. The autoxidized and Mn(VII)-induced samples do not contain metals, but the metal content is 1-2 atom % in samples prepared with Ce(IV) or Cu(II), and ca. 20 atom % in polydopamine prepared in the presence of Fe(III). These differences in the metal content can be explained by the oxidation and complexation properties of the metals using the general model developed. In addition, the nitrogen content is lower in the metal-induced samples. All of the metal oxidants studied can be used to rapidly prepare polydopamine at room temperature, but the possible influence of the metal content and nitrogen loss should be taken into account

Transferrin-targeted porous silicon nanoparticles reduce glioblastoma cell migration across tight extracellular space

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.</p

Hierarchical structured and programmed vehicles deliver drugs locally to inflamed sites of intestine

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.Peer reviewe

Fabrication and Characterization of Drug-Loaded Conductive Poly(glycerol sebacate)/Nanoparticle-Based Composite Patch for Myocardial Infarction Applications

Heart tissue engineering is critical in the treatment of myocardial infarction, which may benefit from drug-releasing smart materials. In this study, we load a small molecule (3i-1000) in new biodegradable and conductive patches for application in infarcted myocardium. The composite patches consist of a biocompatible elastomer, poly(glycerol sebacate) (PGS), coupled with collagen type I, used to promote cell attachment. In addition, polypyrrole is incorporated because of its electrical conductivity and to induce cell signaling. Results from the in vitro experiments indicate a high density of cardiac myoblast cells attached on the patches, which stay viable for at least 1 month. The degradation of the patches does not show any cytotoxic effect, while 3i-1000 delivery induces cell proliferation. Conductive patches show high blood wettability and drug release, correlating with the rate of degradation of the PGS matrix. Together with the electrical conductivity and elongation characteristics, the developed biomaterial fits the mechanical, conductive, and biological demands required for cardiac treatment.</p

Multistage signal-interactive nanoparticles improve tumor targeting through efficient nanoparticle-cell communications

Supramolecular & Biomaterials Chemistr

Hierarchical structured and programmed vehicles deliver drugs locally to inflamed sites of intestine

Orally administrable drug delivery vehicles are developed to manage incurable inflammatory bowel disease (IBD), however, their therapeutic outcomes are compromised by the side effects of systemic drug exposure. Herein, we use hyaluronic acid functionalized porous silicon nanoparticle to bridge enzyme-responsive hydrogel and pH-responsive polymer, generating a hierarchical structured (nano-in-nano-in-micro) vehicle with programmed properties to fully and sequentially overcome the multiple obstacles for efficiently delivering drugs locally to inflamed sites of intestine. After oral administration, the pH-responsive matrix protects the embedded hybrid nanoparticles containing drug loaded hydrogels against the spatially variable physiological environments of the gastrointestinal tract until they reach the inflamed sites of intestine, preventing premature drug release. The negatively charged hybrid nanoparticles selectively target the inflamed sites of intestine, and gradually release drug in response to the microenvironment of inflamed intestine. Overall, the developed hierarchical structured and programmed vehicles load, protect, transport and release drugs locally to inflamed sites of intestine, contributing to superior therapeutic outcomes. Such strategy could also inspire the development of numerous hierarchical structured vehicles by other porous nanoparticles and stimuli-responsive materials for the local delivery of various drugs to treat plenty of inflammatory gastrointestinal diseases, including IBD, gastrointestinal cancers and viral infections.</p