Towards nanomedicines of the future: Remote magneto-mechanical actuation of nanomedicines by alternating magnetic fields

The paper describes the concept of magneto-mechanical actuation of single-domain magnetic nanoparticles (MNPs) in super-low and low frequency alternating magnetic fields (AMFs) and its possible use for remote control of nanomedicines and drug delivery systems. The applications of this approach for remote actuation of drug release as well as effects on biomacromolecules, biomembranes, subcellular structures and cells are discussed in comparison to conventional strategies employing magnetic hyperthermia in a radio frequency (RF) AMF. Several quantitative models describing interaction of functionalized MNPs with single macromolecules, lipid membranes, and proteins (e.g. cell membrane receptors, ion channels) are presented. The optimal characteristics of the MNPs and an AMF for effective magneto-mechanical actuation of single molecule responses in biological and bio-inspired systems are discussed. Altogether, the described studies and phenomena offer opportunities for the development of novel therapeutics both alone and in combination with magnetic hyperthermia

Nanoscale engineering of hybrid magnetite–carbon nanofibre materials for magnetic resonance imaging contrast agents

Magnetic nanomaterials show significant promise as contrast agents for magnetic resonance imaging (MRI). We have developed a new highly efficient one-step procedure for the synthesis of magnetically- functionalised hollow carbon nanofibres, where (i) the carbon nanofibres act as both a template and a support for the nucleation and growth of magnetite nanoparticles and (ii) the structural (size, dispersity and morphology) and functional (magnetisation and coercivity) properties of the magnetic nanoparticles formed on nanofibres are strictly controlled by the mass ratio of the magnetite precursor to the nanofibres and the solvent employed during synthesis. We have shown that our magnetite-nanofibre materials are effectively solubilised in water resulting in a stable suspension that has been employed as a ‘‘negative’’ MRI contrast agent with an excellent transverse relaxivity (r2) of (268 13) mM s 1, surpassing current commercial materials and state-of-the-art magnetic nanoscale platforms in performance for MRI contrast at high magnetic fields. The preparation and evaluation of this unique hybrid nanomaterial represents a critical step towards the realisation of a highly efficient ‘‘smart’’ MRI theranostic agent – a material that allows for the combined diagnosis (with MRI), treatment (with magnetic targeting) and follow-up of a disease (with MRI) – currently in high demand for various clinical applications, including stratified nanomedicine

Stop-frame filming and discovery of reactions at the single-molecule level by transmission electron microscopy

We report an approach – named chemTEM – to follow chemical transformations at the single-molecule level with the electron beam of a transmission electron microscope (TEM) applied as both a tuneable source of energy and a sub-Angstrom imaging probe. Deposited on graphene, disk-shaped perchlorocoronene molecules are precluded from intermolecular interactions. This allows monomolecular transformations to be studied at the single-molecule level in real time and reveals chlorine elimination and reactive aryne formation as a key initial stage of multi-step reactions initiated by the 80 keV e-beam. Under the same conditions, perchlorocoronene confined within a nanotube cavity, where the molecules are situated in very close proximity to each other, enables imaging of intermolecular reactions, starting with the Diels-Alder cycloaddition of a generated aryne, followed by rearrangement of the angular adduct to a planar polyaromatic structure and the formation of a perchlorinated zigzag nanoribbon of graphene as the final product. ChemTEM enables the entire process of polycondensation, including the formation of metastable intermediates, to be captured in a one-shot ‘movie’. A molecule with a similar size and shape but with a different chemical composition, octathio[8]circulene, under the same conditions undergoes another type of polycondensation via thiyl biradical generation and subsequent reaction leading to polythiophene nanoribbons with irregular edges incorporating bridging sulphur atoms. Graphene or carbon nanotubes supporting the individual molecules during chemTEM studies ensure that the elastic interactions of the molecules with the e-beam are the dominant forces that initiate and drive the reactions we image. Our ab initio DFT calculations explicitly incorporating the e-beam in the theoretical model correlate with the chemTEM observations and give a mechanism for direct control not only of the type of the reaction but also of the reaction rate. Selection of the appropriate e-beam energy and control of the dose rate in chemTEM enabled imaging of reactions on a timeframe commensurate with TEM image capture rates, revealing atomistic mechanisms of previously unknown processes

Direct reagentless detection of the affinity binding of recombinant His-tagged firefly luciferase with a nickel-modified gold electrode

The direct reagentless electrochemical detection of recombinant firefly luciferase binding with a gold electrode modified with nickel complex of 1,16-di[4-(2,6-dihydroxycarbonyl)pyridyl]-1,16-dioxa-8,9-dithiahexadecane has been carried out.Funding Agencies|Russian Foundation for Basic Research [09-03-00775-a]</p

Apoptotic MSCs and MSC-Derived Apoptotic Bodies as New Therapeutic Tools

Over the past two decades, mesenchymal stem cells (MSCs) have shown promising therapeutic effects both in preclinical studies (in animal models of a wide range of diseases) and in clinical trials. However, the efficacy of MSC-based therapy is not always predictable. Moreover, despite the large number of studies, the mechanisms underlying the regenerative potential of MSCs are not fully elucidated. Recently, it has been reliably established that transplanted MSCs can undergo rapid apoptosis and clearance from the recipient&rsquo;s body, still exhibiting therapeutic effects, especially those associated with their immunosuppressive/immunomodulating properties. The mechanisms underlying these effects can be mediated by the efferocytosis of apoptotic MSCs by host phagocytic cells. In this concise review, we briefly describe three types of MSC-generated extracellular vesicles, through which their therapeutic functions can potentially be carried out; we focused on reviewing recent data on apoptotic MSCs and MSC-derived apoptotic bodies (MSC-ApoBDs), their functions, and the mechanisms of their therapeutic effects

In Silico Studies on Pharmacokinetics and Neuroprotective Potential of ²⁵Mg²⁺: Releasing Nanocationites - Background and Perspectives

Sharp blood circulation disorders are known for their capability to promote such abundant and hardly treatable pathologies as myocardium infarction and the ischemic brain stroke (“insult”). Noteworthy, the stroke — related brain tissue metabolic damages involve an essential ATP deplete clash along with a suppression of brain specific nucleotide — associated kinases and ATP synthase, both Mg2+ — dependent complex enzyme “machineries”. This itself makes the latter’s a legitimate target for some advanced pharmaceuticals as long as the drug — induced overstimulation of corresponding enzymatic activity is the case. Thus, magnetic isotope effects (MIE) of the nuclear spin possessing paramagnetic 25Mg2+ ions might modulate the brain creatine kinase, alfa-glycerophosphate kinase and pyruvate kinase catalytic activities in a way of a remarkable ATP hyperproduction required to compensate the hypoxia caused acute metabolic breakdown. To realize the Magnesium-25 pharmacological potential, a low-toxic amphiphilic cationite nanoparticles were introduced lately. Particularly, the Magnesium — releasing porphyrin-fullerene nanoadduct (cyclohexyl-C60-porphyrin, PMC16) has been proposed to meet expectations dealing with a targeted delivery of 25Mg2+ towards the brain ischemia surrounding areas. In order to optimize a multi-step [25Mg2+]4PMC16 preclinical trial scenario, the In Silico algorithms are to be developed and analyzed. In this study, these algorithms are in a focus with a special emphasize on a novel combination of slightly modified Gompertzian equation systems and a non-Markov population dynamics concept. This In Silico approach takes into account some literature-available patterns of brain hypoxia pathogenesis, the resulted simulation model could be considered as a promising tool for further research on experimental nanopharmacology of the ischemic stroke

Low-Frequency Dynamic Magnetic Fields Decrease Cellular Uptake of Magnetic Nanoparticles

Magnetic nanoparticles have gained attention as a potential structure for therapy and diagnosing oncological diseases. The key property of the magnetic nanoparticles is the ability to respond to an external magnetic field. It is known that magnetofection causes an increase in the cellular uptake of RNA and DNA in complexes with magnetic nanoparticles in the presence of a permanent magnetic field. However, the influence of a dynamic magnetic field on the internalization of MNPs is not clear. In this work, we propose the idea that applying external low-frequency dynamic magnetic fields may decrease the cellular uptake, such as macrophages and malignant neuroblastoma. Using fluorescence microscopy and atomic emission spectroscopy, we found that oscillating magnetic fields decreased the cellular uptake of magnetic nanoparticles compared to untreated cells by up to 46%. In SH-SY5Y tumor cells and macrophage RAW264.7 cells, the absolute values of Fe per cell differed by 0.10 pg/cell and 0.33 pg/cell between treated and untreated cells, respectively. These results can be applied in the control of the cellular uptake in different areas of biomedicine

Heterotypic Multicellular Spheroids as Experimental and Preclinical Models of Sprouting Angiogenesis

Sprouting angiogenesis is the common response of live tissues to physiological and pathological angiogenic stimuli. Its accurate evaluation is of utmost importance for basic research and practical medicine and pharmacology and requires adequate experimental models. A variety of assays for angiogenesis were developed, none of them perfect. In vitro approaches are generally less physiologically relevant due to the omission of essential components regulating the process. However, only in vitro models can be entirely non-xenogeneic. The limitations of the in vitro angiogenesis assays can be partially overcome using 3D models mimicking tissue O2 and nutrient gradients, the influence of the extracellular matrix (ECM), and enabling cell-cell interactions. Here we present a review of the existing models of sprouting angiogenesis that are based on the use of endothelial cells (ECs) co-cultured with perivascular or other stromal cells. This approach provides an excellent in vitro platform for further decoding of the cellular and molecular mechanisms of sprouting angiogenesis under conditions close to the in vivo conditions, as well as for preclinical drug testing and preclinical research in tissue engineering and regenerative medicine