The potential of magnetic hyperthermia for triggering the differentiation of cancer cells

Magnetic hyperthermia is a potential technique for cancer therapy that exploits heat generated by magnetic nanoparticles to kill cancerous cells. Many studies have shown that magnetic hyperthermia is effective at killing cancer cells both in vitro and in vivo, however little attention has been paid to the cellular functioning of the surviving cells. We report here new evidence demonstrating the onset of thermally triggered differentiation in osteosarcoma cancer cells that survive magnetic hyperthermia treatment. This raises the possibility that in addition to causing cell death, magnetic hyperthermia could induce surviving cancer cells to form more mature cell types and thereby inhibit their capacity to self-renew. Such processes could prove to be as important as cell death when considering magnetic hyperthermia for treating cancer

Probing magnetization dynamics of iron oxide nanoparticles using a point-probe magneto-optical method

Magnetic nanoparticles (MNPs) are promising as local heat generators for magnetic hyperthermia under AC magnetic fields. The heating efficacy of MNPs is determined by the AC hysteresis loop area, which in turn is affected by the dynamic magnetic properties of the nanoparticles. Whilst inductive-based AC magnetometers can measure the average magnetic behavior of samples, the use of the magneto-optical Faraday effect with a focused laser spot allows point-probe measurements to be made, and without some of the magnetic field limitations imposed by inductive methods. In this work, the AC magnetic properties of different sized iron oxide MNPs in suspension were measured by AC magnetometry and AC susceptibility techniques. AC hysteresis loops measured by magneto-optical magnetometry were validated using a commercial inductive AC magnetometer, and compared to the magnetization relaxation behavior revealed by fitting the AC susceptibility data. The spatial sensitivity of the point-probe magneto-optical method is also demonstrated by measuring the AC hysteresis loop from large (>1 μm) MNP aggregates dried onto glass slides. These aggregated particles are found to be magnetically softer than in their suspension form, suggesting interparticle coupling mechanisms could occur when the nanoparticles form dense aggregates

Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy

Neuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson’s disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues

The potential of magnetic hyperthermia for triggering the differentiation of cancer cells

Magnetic hyperthermia is a potential technique for cancer therapy that exploits heat generated by magnetic nanoparticles to kill cancerous cells. Many studies have shown that magnetic hyperthermia is effective at killing cancer cells both in vitro and in vivo, however little attention has been paid to the cellular functioning of the surviving cells. We report here new evidence demonstrating the onset of thermally triggered differentiation in osteosarcoma cancer cells that survive magnetic hyperthermia treatment. This raises the possibility that in addition to causing cell death, magnetic hyperthermia could induce surviving cancer cells to form more mature cell types and thereby inhibit their capacity to self-renew. Such processes could prove to be as important as cell death when considering magnetic hyperthermia for treating cancer

Iron biochemistry is correlated with amyloid plaque morphology in an established mouse model of Alzheimer’s disease

A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aβ. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Aβ-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD

Controlling human platelet activation with calcium-binding nanoparticles

We introduce a neural method that is able to fuse concepts from a knowledge base with the context information for the task of grouping of aspect terms. Rather than only using context information, we use the corresponding concepts of aspect terms as additional information for aspect terms representation. We also introduce a location-based attention mechanism for accurately representing context features. As both the concept and the aspect term are same level features, i.e. aspect level features, we develop a model with gating mechanism to fuse them together. All of the above features are fed into a parallel metric learning network which has the ability to learn an easier grouping representation of samples. Experimental results demonstrate that our approach outperforms different baselines and model variants on five datasets

Metal ion binding to the amyloid beta monomer studied by native top-down FTICR mass spectrometry

Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of the full-length amyloid β (1-42) monomer with a range of (patho)physiologically relevant metal cations using native Fourier transform ion cyclotron resonance mass spectrometry and three different fragmentation methods—collision-induced dissociation, electron capture dissociation, and infrared multiphoton dissociation—all yielding consistent results. Amyloid β is of particular interest as its oligomerization and aggregation are major events in the etiology of Alzheimer’s disease, and it is known that interactions between the peptide and bioavailable metal cations have the potential to significantly damage neurons. Those metals which exhibited the strongest binding to the peptide (Cu2+, Co2+, Ni2+) all shared a very similar binding region containing two of the histidine residues near the N-terminus (His6, His13). Notably, Fe3+ bound to the peptide only when stabilized toward hydrolysis, aggregation, and precipitation by a chelating ligand, binding in the region between Ser8 and Gly25. We also identified two additional binding regions near the flexible, hydrophobic C-terminus, where other metals (Mg2+, Ca2+, Mn2+, Na+, and K+) bound more weakly—one centered on Leu34, and one on Gly38. Unexpectedly, collisional activation of the complex formed between the peptide and [CoIII(NH3)6]3+ induced gas-phase reduction of the metal to CoII, allowing the peptide to fragment via radical-based dissociation pathways. This work demonstrates how native mass spectrometry can provide new insights into the interactions between amyloid β and metal cations

Harnessing the extracellular bacterial production of nanoscale cobalt ferrite with exploitable magnetic properties

Nanoscale ferrimagnetic particles have a diverse range of uses from directed cancer therapy and drug delivery systems to magnetic recording media and transducers. Such applications require the production of monodisperse nanoparticles with well-controlled size, composition, and magnetic properties. To fabricate these materials purely using synthetic methods is costly in both environmental and economical terms. However, metal-reducing microorganisms offer an untapped resource to produce these materials. Here, the Fe(III)-reducing bacterium Geobacter sulfurreducens is used to synthesize magnetic iron oxide nanoparticles. A combination of electron microscopy, soft X-ray spectroscopy, and magnetometry techniques was employed to show that this method of biosynthesis results in high yields of crystalline nanoparticles with a narrow size distribution and magnetic properties equal to the best chemically synthesized materials. In particular, it is demonstrated here that cobalt ferrite (CoFe2O4) nanoparticles with low temperature coercivity approaching 8 kOe and an effective anisotropy constant of ∼106 erg cm−3 can be manufactured through this biotechnological route. The dramatic enhancement in the magnetic properties of the nanoparticles by the introduction of high quantities of Co into the spinel structure represents a significant advance over previous biomineralization studies in this area using magnetotactic bacteria. The successful production of nanoparticulate ferrites achieved in this study at high yields could open up the way for the scaled-up industrial manufacture of nanoparticles using environmentally benign methodologies

'Stealth' nanoparticles evade neural immune cells but also evade major brain cell populations: Implications for PEG-based neurotherapeutics

Surface engineering to control cell behavior is of high interest across the chemical engineering, drug delivery and biomaterial communities. Defined chemical strategies are necessary to tailor nanoscale protein interactions/adsorption, enabling control of cell behaviors for development of novel therapeutic strategies. Nanoparticle-based therapies benefit from such strategies but particle targeting to sites of neurological injury remains challenging due to circulatory immune clearance. As a strategy to overcome this barrier, the use of stealth coatings can reduce immune clearance and prolong circulatory times, thereby enhancing therapeutic capacity. Polyethylene glycol (PEG) is the most widely-used stealth coating and facilitates particle accumulation in the brain. However, once within the brain, the mode of handling of PEGylated particles by the resident immune cells of the brain itself (the ‘microglia’) is unknown. This is a critical question as it is well established that microglia avidly sequester nanoparticles, limiting their bioavailability and posing a major translational barrier. If PEGylation can be proved to promote evasion of microglia, then this information will be of high value in developing tailored nanoparticle-based therapies for neurological applications. Here, we have conducted the first comparative study of uptake of PEGylated particles by all the major (immune and non-immune) brain cell types. We prove for the first time that PEGylated nanoparticles evade major brain cell populations — a phenomenon which will enhance extracellular bioavailability. We demonstrate changes in protein coronas around these particles within biological media, and discuss how surface chemistry presentation may affect this process and subsequent cellular interactions