Alexander G. Majouga

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.

Core–shell–corona doxorubicin-loaded superparamagnetic Fe3O4 nanoparticles for cancer theranostics

Superparamagnetic iron oxide magnetic nanoparticles (MNPs) are successfully used as contrast agents in magnetic-resonance imaging. They can be easily functionalized for drug delivery functions, demonstrating great potential for both imaging and therapeutic applications. Here we developed new pH-responsive theranostic core-shell-corona nanoparticles consisting of superparamagentic Fe3O4 core that displays high T2 relaxivity, bovine serum albumin (BSA) shell that binds anticancer drug, doxorubicin (Dox) and poly(ethylene glycol) (PEG) corona that increases stability and biocompatibility. The nanoparticles were produced by adsorption of the BSA shell onto the Fe3O4 core followed by crosslinking of the protein layer and subsequent grafting of the PEG corona using monoamino-terminated PEG via carbodiimide chemistry. The hydrodynamic diameter, zeta-potential, composition and T2 relaxivity of the resulting nanoparticles were characterized using transmission electron microscopy, dynamic light scattering, thermogravimetric analysis and T2-relaxometry. Nanoparticles were shown to absorb Dox molecules, possibly through a combination of electrostatic and hydrophobic interactions. The loading capacity (LC) of the nanoparticles was 8 wt.%. The Dox loaded nanoparticles release the drug at a higher rate at pH 5.5 compared to pH 7.4 and display similar cytotoxicity against C6 and HEK293 cells as the free Dox.

Mixed Valence Copper(I,II) Binuclear Complexes with Unexpected Structure: Synthesis, Biological Properties and Anticancer Activity

We have synthesized and characterized a panel of new binuclear mixed valence Cu(I,II) complexes containing substituted 2-alkylthio-5-arylmethylene-4H-imidazolin-4-ones with unusual structure. These complexes are shown to be cytotoxic for various cell lines. We have found that these compounds did not intercalate DNA, inhibited number of polymerases (telomerase predominantly), accumulated in the cell nucleus, and caused DNA degradation. Preliminary studies revealed that lead compound inhibited human breast adenocarcinoma growth in mice model.

Changing the Enzyme Reaction Rate in Magnetic Nanosuspensions by a Non‐Heating Magnetic Field

Weak magnetic fields (< 1 T) are known to change the paths and kinetics of some radical chemical reactions at room temperature through spin conversion of short-lived radical pairs. [1] Magnetic fields were also used to tune enzyme activity (oxidation of glucose). Specifically, exposure of magnetic nanoparticles functionalized with enzymes to magnetic field allowed the movement of particles in proximity to electrode, thus activating the enzyme. [2] Moreover, radio-frequency (RF) alternating current (AC) magnetic fields can induce the heating of single-domain magnetic nanoparticles (MNPs), and this can be used in magnetic hyperthermia to kill tumors. [3] Herein we describe a distinct effect of non-heating superlow-frequency magnetic fields as well as more conventional RF magnetic fields on the kinetics of chemical reactions catalyzed by the enzymes a-chymotrypsin (ChT) or bgalactosidase (b-GaL) immobilized on nanoscale MNP aggregates. Magnetite MNPs (7 to 12 nm diameter) were synthesized by reducing tris(acetylacetonato)iron(III), then they were coated with anionic poly(ethylene glycol)-bpolyacrylate (PEG-PAA), or poly(ethylene glycol)-b-polymethacrylate (PEG-PMA) copolymers. The polymers were bound to the magnetite surfaces by the carboxylate groups. [4] According to thermogravimetric analysis, the content of Fe3O4 in both coated MNP materials was about 35 wt %, and this was in excellent agreement with that measured by inductively coupled plasma-mass spectrometry. Upon dispersion in water (pH 6.5), they formed nanoscale, negatively charged aggregates (hydrodynamic intensity average diameters and zeta potentials of 194 nm, 70 mV and 39 nm, 49 mV for PEG-PAA/MNP and PEG-PMA/MNP, respectively, as determined by dynamic light scattering). Based on TEM, they contained clusters of 7 to 20 MNP grains. Enzymes were conjugated to these aggregates using 1-ethyl-3-(3dimethylaminopropyl)-carbodiimide and N-hydroxysulfosuccinimide to couple amines on the protein to carboxylic acids on the copolymer (Scheme 1).

Investigation of the Interactions and Bonding between Carbon and Group VIII Metals at the Atomic Scale

The nature and dynamics of bonding between Fe, Ru, Os, and single-walled carbon nanotubes (SWNTs) is studied by aberration-corrected high-resolution transmission electron microscopy (AC-HRTEM). The metals catalyze a wide variety of different transformations ranging from ejection of carbon atoms from the nanotube sidewall to the formation of hollow carbon shells or metal carbide within the SWNT, depending on the nature of the metal. The electron beam of AC-HRTEM serves the dual purpose of providing energy to the specimen and simultaneously enabling imaging of chemical transformations. Careful control of the electron beam parameters, energy, flux, and dose allowed direct comparison between the metals, demonstrating that their chemical reactions with SWNTs are determined by a balance between the cohesive energy of the metal particles and the strength of the metal-carbon σ- or π-bonds. The pathways of transformations of a given metal can be drastically changed by applying different electron energies (80, 40, or 20 keV), thus demonstrating AC-HRTEM as a new tool to direct and study chemical reactions. The understanding of interactions and bonding between SWNT and metals revealed by AC-HRTEM at the atomic level has important implications for nanotube-based electronic devices and catalysis.

Design, synthesis and biological evaluation of novel potent MDM2/p53 small-molecule inhibitors.

Regioselective synthesis, biological evaluation and 3D-molecular modeling for a series of novel diastereomeric 2-thioxo-5H-dispiro[imidazolidine-4,3-pyrrolidine-2,3-indole]-2,5(1H)-diones are described. The studied compounds have been tentatively identified as potent small molecule MDM2/p53 PPI inhibitors and can therefore be reasonably regarded as promising anticancer therapeutics.

Enzyme-functionalized gold-coated magnetite nanoparticles as novel hybrid nanomaterials: Synthesis, purification and control of enzyme function by low-frequency magnetic field

The possibility of remotely inducing a defined effect on NPs by means of electromagnetic radiation appears attractive. From a practical point of view, this effect opens horizons for remote control of drug release systems, as well as modulation of biochemical functions in cells. Gold-coated magnetite nanoparticles are perfect candidates for such application. Herein, we have successfully synthesized core-shell NPs having magnetite cores and gold shells modified with various sulphur containing ligands and developed a new, simple and robust procedure for the purification of the resulting nanoparticles. The carboxylic groups displayed at the surface of the NPs were utilized for NP conjugation with a model enzyme (ChT). In the present study, we report the effect of the low-frequency AC magnetic field on the catalytic activity of the immobilized ChT. We show that the enzyme activity decreases upon exposure of the NPs to the field.

Theranostic multimodal potential of magnetic nanoparticles actuated by non-heating low frequency magnetic field in the new-generation nanomedicine

The scope of this review involves one of the most promising branches of new-generation biomedicine, namely magnetic nanotheranostics using remote control of functionalized magnetic nanoparticles (f-MNPs) by means of alternating magnetic fields (AMFs). The review is mainly focused on new approach which utilizes non-heating low frequency magnetic fields (LFMFs) for nanomechanical actuation of f-MNPs. This approach is compared to such traditional ones as magnetic resonance imaging (MRI) and radio-frequency (RF) magnetic hyperthermia (MH) which utilize high frequency heating AMF. The innovative principles and specific models of non-thermal magnetomechanical actuation of biostructures by MNP rotational oscillations in LFMF are described. The discussed strategy allows biodistribution monitoring in situ, delivering drugs to target tissues and releasing them with controlled rate, controlling biocatalytic reaction kinetics, inducing malignant cell apoptosis, and more. Optimization of both LFMF and f-MNP parameters may lead to dramatic improvement of treatment efficiency, locality, and selectivity on molecular or cellular levels and allow implementing both drug and drugless, i.e., pure nanomechanical therapy, in particular cancer therapy. The optimal parameters within this approach differ significantly from those used in MH or MRI because of the principal difference in the f-MNP actuation modes. It is shown that specifically designed high gradient, steady magnetic field enables diagnostic and therapeutic LFMF impact localization in the deep tissues within the area ranging from a millimeter to a few centimeters and 3D scanning of affected region, if necessary.

Effects of cadmium chloride on the functional state of human intestinal cells

Toxic effects of cadmium chloride in concentration range from 1 to 300 μM on differentiated human intestinal epithelial Caco-2 cells after three hours of exposure were investigated. Processes of disorganization of the actin cytoskeleton associated with the toxic effects of cadmium were characterized by fluorescent microscopy. The cadmium-induced activation of cellular stress response processes (changes in the mRNA expression of caspase-3, heat-shock and oxidative stress genes) has been demonstrated. The study revealed dose-dependent changes in mRNA expression levels of proteins involved in the formation of adherens (E-Cadherin and p120 catenin) and tight intercellular junction contacts (Claudin 4 and ZO1). The time- and concentration-dependent trend of cell monolayer transepithelial resistance lowering, characterizing the loss of intercellular contacts density with prolongation of cell exposure cadmium chloride was estimated. Results indicates that proteins associated with tight and adhesion junctions are primary targets of cadmium. Amongst genes involved in cell junction formation, the genes encoding E-Cadherin and p120-catenin proved to be the most sensitive to cadmium influence.

Coordination Compounds of S- and Se-Containing Organic Ligands as Catalysts of Oxidation Reaction Under N2O Action

Abstract Nitrous oxide (N2O) would be preferable to many other oxidants because in the reactions of N2O with organic compounds the only byproduct is N2, which is perfect from the point of view of “green” chemistry. We recently reported a series of new sulfur- and selenoorganic ligands, their coordination compound with Co(II) or Cu(I,II), and the possibility for these complexes to activate nitrous oxide in the oxidation reactions with phosphines and alkenes. The electrochemical data confirm the stability of reduced form of investigated complexes and the capacity of these complexes to associate with nitrous oxide. GRAPHICAL ABSTRACT