Biodegradable zinc-containing mesoporous silica nanoparticles for cancer therapy

Triple-negative breast cancers are extremely aggressive with limited treatment options because of the reduced response of the cancerous cells to hormonal therapy. Here, monodispersed zinc-containing mesoporous silica nanoparticles (MSNPs-Zn) were produced as a tuneable biodegradable platform for delivery of therapeutic zinc ions into cells. We demonstrate that the nanoparticles were internalized by cells, and a therapeutic dose window was identified in which the MSNPs-Zn were toxic to breast cancer cells but not to healthy epithelial (MCF-10a) cells or to murine macrophages. A significant reduction in the viability of triple negative MDA-MB-231 and MCF-7 (ER+) breast cancer cells was seen following 24 h exposure to MSNPs-Zn. The more aggressive MDA-MB-231 cells, with higher metastatic potential, were more sensitive to MSNPs-Zn than the MCF-7 cells. MSNPs-Zn underwent biodegradation inside the cells, becoming hollow structures, as imaged by high-resolution transmission electron microscopy. The mesoporous silica nanoparticles provide a biodegradable vehicle for therapeutic ion release inside cells

Influence of the initial chemical conditions on the rational design of silica particles

The influence of the water content in the initial composition on the size of silica particles produced using the Stöber process is well known. We have shown that there are three morphological regimes defined by compositional boundaries. At low water levels (below stoichiometric ratio of water:tetraethoxysilane), very high surface area and aggregated structures are formed; at high water content (>40 wt%) similar structures are also seen. Between these two boundary conditions, discrete particles are formed whose size are dictated by the water content. Within the compositional regime that enables the classical Stöber silica, the structural evolution shows a more rapid attainment of final particle size than the rate of formation of silica supporting the monomer addition hypothesis. The clearer understanding of the role of the initial composition on the output of this synthesis method will be of considerable use for the establishment of reliable reproducible silica production for future industrial adoption

The α1-adrenergic receptors: diversity of signaling networks and regulation

The α1-adrenergic receptor (AR) subtypes (α1a, α1b, and α1d) mediate several physiological effects of epinephrineand norepinephrine. Despite several studies in recombinant systems and insightfrom genetically modified mice, our understanding of the physiological relevance and specificity of the α1-AR subtypes is still limited. Constitutive activity and receptor oligomerization have emerged as potential features regulating receptor function. Another recent paradigm is that βarrestins and G protein-coupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effects. The aim of this review is to summarize our current knowledge on some recently identified functional paradigms and signaling networks that might help to elucidate the functional diversity of the α1-AR subtypes in various organs

A Computational Approach to Finding Novel Targets for Existing Drugs

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects

Beyond links and chains in food supply: a community OR perspective

This theoretical paper complements traditional OR approaches to improve micro-businesses’ performance. When looking at local micro-businesses, we find that current supply chain and operations theory that focuses on efficiency and economic-based criteria for chain and network integration, is inapplicable and external organisation inappropriate. An illustration shows how traditional modelling exercises may fall short in better-informing independent-minded micro-entrepreneurs on how to collaborate, even though they recognise benefits from such endeavour. The illustration concerns consideration of food micro-producers, not as links constituting a chain, but as members of a community. This paper explores two different approaches to apply Community OR research principles. On one hand, the application of OR methods to phenomena in the ‘community’; on the other, the development of research on ‘community operations’; which are symbolised as C+OR and CO+R respectively. These approaches are associated to two different research languages: of needs and for interactions. Main contributions of this paper are: first, we show that collaboration does not always need shared aims. Second, we offer a circular process where the identification of collective actions may help organisations to improve individually; and vice versa. Third, we suggest how to develop the role of a stronger collective actor by means of collaboration

Cobalt‐containing spherical glass nanoparticles for therapeutic ion release

Bioactive glass nanoparticles (BGNPs) can be internalized by cells, allowing the intracellular release of dissolution products with therapeutic benefit. Different therapeutic ions can be incorporated into the glass network that can promote angiogenesis via simulation of hypoxia conditions and consequent activation of pro-angiogenic genes. Here, novel monodispersed spherical dense BGNPs were obtained by a modified Stöber method with the SiO2–CaO–CoO composition, with diameters of 92 ± 1 nm, with cobalt as the pro-angiogenic ion. The presence of Co2+ species and the role of Co and Ca as network modifiers in the silica glass were confirmed by X-ray photoelectron spectroscopy and 29Si solid-state magic-angle spinning nuclear magnetic resonance, respectively. Controlled Co2+ ion release was observed in culture media, and no cytotoxicity was observed by (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide cell viability assay on human osteosarcoma cells in direct contact with the nanoparticles. This study demonstrated that Co2+ ions can be incorporated into dense and spherical BGNPs, and these materials exhibit great potential as intracellular ion delivery systems with therapeutic properties