Magnetogenetics as a promising tool for controlling cellular signaling pathways.

Magnetogenetics emerges as a transformative approach for modulating cellular signaling pathways through the strategic application of magnetic fields and nanoparticles. This technique leverages the unique properties of magnetic nanoparticles (MNPs) to induce mechanical or thermal stimuli within cells, facilitating the activation of mechano- and thermosensitive proteins without the need for traditional ligand-receptor interactions. Unlike traditional modalities that often require invasive interventions and lack precision in targeting specific cellular functions, magnetogenetics offers a non-invasive alternative with the capacity for deep tissue penetration and the potential for targeting a broad spectrum of cellular processes. This review underscores magnetogenetics' broad applicability, from steering stem cell differentiation to manipulating neuronal activity and immune responses, highlighting its potential in regenerative medicine, neuroscience, and cancer therapy. Furthermore, the review explores the challenges and future directions of magnetogenetics, including the development of genetically programmed magnetic nanoparticles and the integration of magnetic field-sensitive cells for in vivo applications. Magnetogenetics stands at the forefront of cellular manipulation technologies, offering novel insights into cellular signaling and opening new avenues for therapeutic interventions.

Magnetic Nanocomposite Materials Based on Fe3O4 Nanoparticles with Iron and Silica Glycerolates Shell: Synthesis and Characterization.

Novel magnetic nanocomposite materials based on Fe3O4 nanoparticles coated with iron and silica glycerolates (MNP@Fe(III)Glyc and MNP@Fe(III)/SiGlyc) were obtained. The synthesized nanocomposites were characterized using TEM, XRD, TGA, VMS, Mössbauer and IR spectroscopy. The amount of iron and silica glycerolates in the nanocomposites was calculated from the Mössbauer spectroscopy, ICP AES and C,H-elemental analysis. Thus, it has been shown that the distribution of Fe in the shell and core for MNP@Fe(III)Glyc and MNP@Fe(III)/SiGlyc is 27:73 and 32:68, respectively. The synthesized nanocomposites had high specific magnetization values and a high magnetic response to the alternating magnetic field. The hydrolysis of shells based on Fe(III)Glyc and Fe(III)/SiGlyc in aqueous media has been studied. It has been demonstrated that, while the iron glycerolates shell of MNP@Fe(III)Glyc is resistant to hydrolysis, the silica glycerolates shell of MNP@Fe(III)/SiGlyc is rather labile and hydrolyzed by 76.4% in 24 h at 25 °C. The synthesized materials did not show cytotoxicity in in vitro experiments (MTT-assay). The data obtained can be used in the design of materials for controlled-release drug delivery.

Absolute Stereochemistry and Cytotoxic Effects of Vismione E from Marine Sponge-Derived Fungus Aspergillus sp. 1901NT-1.2.2.

The metabolic profile of the Aspergillus sp. 1901NT-1.2.2 sponge-associated fungal strain was investigated using the HPLC MS technique, and more than 23 peaks in the HPLC MS chromatogram were detected. Only two minor peaks were identified as endocrocin and terpene derivative MS data from the GNPS database. The main compound was isolated and identified as known anthraquinone derivative vismione E. The absolute stereochemistry of vismione E was established for the first time using ECD and quantum chemical methods. Vismione E showed high cytotoxic activity against human breast cancer MCF-7 cells, with an IC50 of 9.0 µM, in comparison with low toxicity for normal human breast MCF-10A cells, with an IC50 of 65.3 µM. It was found that vismione E inhibits MCF-7 cell proliferation and arrests the cell cycle in the G1 phase. Moreover, the negative influence of vismione E on MCF-7 cell migration was detected. Molecular docking of vismione E suggested the IMPDH2 enzyme as one of the molecular targets for this anthraquinone derivative.

5-Amino-2-aryl-2H-1,2,3-triazole-4-carboxamides: Unique AIEE-gens and selective Hg2+ fluorosensors.

A series of fluorescent sensors based on small molecule were designed and fully characterised, demonstrating AIEE effect and revealing an outstanding ability to selectively detect Hg2+ ions. The structural and electronic properties were studied through quantum chemical calculations at (Time-Dependent) Density Functional Theory ((TD)-DFT) level. Carboxamides of 2-Aryl-1,2,3-Triazoles (CATs) showed significant differences in their photophysical properties depending on the structure of the substituent at amino function on the C5-atom in the heterocycle. When the tert-cycloalkylamino group (pyrrolidine, piperidine, azepane) was attached, the triazoles exhibited highly intensive blue fluorescence, with quantum yields (QYs) up to 95 % and lifetime up to 6.9 ns in different solvents, whereas the QYs of congeners bearing secondary alkylaminogroups (viz., NHMe, NHC6H11-cyclo) indicate low QYs (1-10 %). Nevertheless, all types of the obtained fluorophores demonstrated excellent AIEE effect and formed fluorescent nanoparticles in a binary mixtures of organic solvents and water. The introduction of the carboxamide function enhances the sensing properties of 2-aryl-1,2,3-triazoles, providing a selective fluorescence quenching reaction in the presence of Hg2+. The fluorescence intensity of the CATs declines with the addition of 1.0 eq. of Hg2+ into DMSO-water (v/v, 1:9). The other cations used did not induce any appreciable changes in fluorescence intensity. The CATs form a complex with Hg2+ with highly specific detection for Hg2+ over other competitive metal ions: the detection limits were determined to be 0.23 and 0.15 µM for the CATs 1b and 2c. The reverse effect was registered with the addition of ethylene diamine sodium salt; meanwhile, the CATs demonstrated more effective coordination with Hg2+ in comparison with cysteine. This last finding, as well as the ability to detect Hg2+, is very valuable for application within biology and medicine.

Peptide ligands on the PEGylated nanoparticle surface and human serum composition are key factors for the interaction between immune cells and nanoparticles.

The architecture of a nanoparticles' surface formed due to a modification with a ligand and protein corona formation in biofluids is critical for interactions with cells in vivo. Here we studied interactions of immune cells with magnetic nanoparticles (MNPs) covalently modified with polyethylene glycol (PEG) and their counterparts conjugated with peptides: a pH (low) insertion peptide (pHLIP) and cycloRGD as a targeting ligand in human serum. The conjugation of MNPs-PEG with pHLIP, but not with cycloRGD, enhanced the association of these particles with mononuclear phagocytic cells in vitro and in vivo. We did not find a clear difference in protein corona composition between the pHLIP-modified and parental PEGylated nanoparticles. Analysis of the effect of autologous human serum on MNP uptake by monocytes showed that the efficiency of endocytosis varies among healthy donors and depends on intrinsic properties of serum. Nevertheless, using classic blood, coagulation, biochemical tests, and anti-PEG IgG serum level, we failed to identify the cause of the observed interdonor variation. These individual differences should be taken into consideration during testing of nanotherapeutics.

New TEMPO-Appended 2,2'-Bipyridine-Based Eu(III), Tb(III), Gd(III) and Sm(III) Complexes: Synthesis, Photophysical Studies and Testing Photoluminescence-Based Bioimaging Abilities.

Linked to Alzheimer's disease (AD), amyloids and tau-protein are known to contain a large number of cysteine (Cys) residues. In addition, certain levels of some common biogenic thiols (cysteine (Cys), homocysteine (Hcy), glutathione (GSH), etc.) in biological fluids are closely related to AD as well as other diseases. Therefore, probes with a selective interaction with the above-mentioned thiols can be used for the monitoring and visualizing changes of (bio)thiols in the biological fluids as well as in the brain of animal models of Alzheimer's disease. In this study, new Eu(III), Tb(III), Gd(III) and Sm(III) complexes of 2,2'-bipyridine ligands containing TEMPO fragments as receptor units for (bio)thiols are reported. The presence of free radical fragments of the ligand in the complexes was proved by using the electronic paramagnetic resonance (EPR) method. Among all the complexes, the Eu(III) complex turned out to be the most promising one as luminescence- and spin-probe for the detection of biogenic thiols. The EPR and fluorescent titration methods showed the interaction of the resulting complex with free Cys and GSH in solution. To study the practical applicability of the probes for the monitoring of AD in-vivo, by using the above-mentioned Eu(III)-based probe, the staining of the brain of mice with amyloidosis and Vero cell cultures supplemented with the cysteine-enriched medium was studied as well as the fluorescence titration of Bovine Serum Albumin, BSA (as the model for the thiol moieties containing protein), was carried out. Based on the results of fluorescence titration, the formation of a non-covalent inclusion complex between the above-mentioned Eu(III) complex and BSA was suggested.

Effect of the Silica-Magnetite Nanocomposite Coating Functionalization on the Doxorubicin Sorption/Desorption.

A series of new composite materials based on Fe3O4 magnetic nanoparticles coated with SiO2 (or aminated SiO2) were synthesized. It has been shown that the use of N-(phosphonomethyl)iminodiacetic acid (PMIDA) to stabilize nanoparticles before silanization ensures the increased content of a SiO2 phase in the Fe3O4@SiO2 nanocomposites (NCs) in comparison with materials obtained under similar conditions, but without PMIDA. It has been demonstrated for the first time that the presence of PMIDA on the surface of NCs increases the level of Dox loading due to specific binding, while surface modification with 3-aminopropylsilane, on the contrary, significantly reduces the sorption capacity of materials. These regularities were in accordance with the results of quantum chemical calculations. It has been shown that the energies of Dox binding to the functional groups of NCs are in good agreement with the experimental data on the Dox sorption on these NCs. The mechanisms of Dox binding to the surface of NCs were proposed: simultaneous coordination of Dox on the PMIDA molecule and silanol groups at the NC surface leads to a synergistic effect in Dox binding. The synthesized NCs exhibited pH-dependent Dox release, as well as dose-dependent cytotoxicity in in vitro experiments. The cytotoxic effects of the studied materials correspond to their calculated IC50 values. NCs with a SiO2 shell obtained using PMIDA exhibited the highest effect. At the same time, the presence of PMIDA in NCs makes it possible to increase the Dox loading, as well as to reduce its desorption rate, which may be useful in the design of drug delivery vehicles with a prolonged action. We believe that the data obtained can be further used to develop stimuli-responsive materials for targeted cancer chemotherapy.

Magnetic-Responsive Doxorubicin-Containing Materials Based on Fe3O4 Nanoparticles with a SiO2/PEG Shell and Study of Their Effects on Cancer Cell Lines.

Novel nanocomposite materials based on Fe3O4 magnetic nanoparticles (MNPs) coated with silica and covalently modified by [(3-triethoxysilyl)propyl]succinic acid-polyethylene glycol (PEG 3000) conjugate, which provides a high level of doxorubicin (Dox) loading, were obtained. The efficiency of Dox desorption from the surface of nanomaterials under the action of an alternating magnetic field (AMF) in acidic and neutral media was evaluated. Their high cytotoxicity against tumor cells, as well as the drug release upon application of AMF, which leads to an increase in the cytotoxic effect, was demonstrated.

Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals.

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 µg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking.

Smart Design of a pH-Responsive System Based on pHLIP-Modified Magnetite Nanoparticles for Tumor MRI.

Magnetic Fe3O4 nanoparticles (MNPs) are often used to design agents enhancing contrast in magnetic resonance imaging (MRI) that can be considered as one of the efficient methods for cancer diagnostics. At present, increasing the specificity of the MRI contrast agent accumulation in tumor tissues remains an open question and attracts the attention of a wide range of researchers. One of the modern methods for enhancing the efficiency of contrast agents is the use of molecules for tumor acidic microenvironment targeting, for example, pH-low insertion peptide (pHLIP). We designed novel organosilicon MNPs covered with poly(ethylene glycol) (PEG) and covalently modified by pHLIP. To study the specific features of the binding of pHLIP-modified MNPs to cells, we also obtained nanoconjugates with Cy5 fluorescent dye embedded in the SiO2 shell. The nanoconjugates obtained were characterized by transmission electron microscopy (TEM), attenuated total reflection (ATR), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), dynamic light scattering (DLS), UV and fluorescence spectrometry, thermogravimetric analysis (TGA), CHN elemental analyses, and vibrating sample magnetometry. Low cytotoxicity and high specificity of cellular uptake of pHLIP-modified MNPs at pH 6.4 versus 7.4 (up to 23-fold) were demonstrated in vitro. The dynamics of the nanoconjugate accumulation in the 4T1 breast cancer orthotopically grown in BALB/c mice and MDA-MB231 xenografts was evaluated in MRI experiments. Biodistribution and biocompatibility studies of the obtained nanoconjugate showed no pathological change in organs and in the blood biochemical parameters of mice after MNP administration. A high accumulation rate of pHLIP-modified MNPs in tumor compared with PEGylated MNPs after their intravenous administration was demonstrated. Thus, we propose a promising approach to design an MRI agent with the tumor acidic microenvironment targeting ability.

Variation in tumor pH affects pH-triggered delivery of peptide-modified magnetic nanoparticles.

Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pH 6.4 than at pH 7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.

L-Lysine-modified Fe3O4 nanoparticles for magnetic cell labeling.

The efficiency of magnetic labeling with L-Lys-modified Fe3O4 magnetic nanoparticles (MNPs) and the stability of magnetization of rat adipose-derived mesenchymal stem cells, lineage-negative (Lin(-)) hematopoietic progenitor cells from mouse bone marrow and human leukemia K562 cells were studied. For this purpose, covalent modification of MNPs with 3-aminopropylsilane and N-di-Fmoc-L-lysine followed by removal of N-protecting groups was carried out. Since the degree of hydroxylation of the surface of the starting nanoparticles plays a crucial role in the silanization reaction and the possibility of obtaining stable colloidal solutions. In present work we for the first time performed a comparative qualitative and quantitative evaluation of the number of adsorbed water molecules and hydroxyl groups on the surface of chemically and physically obtained Fe3O4 MNPs using comprehensive FTIR spectroscopy and thermogravimetric analysis. The results obtained can be further used for magnetic labeling of cells in experiments in vitro and in vivo.

Supporting data and methods for the characterization of iron oxide nanoparticles conjugated with pH-(low)-insertion peptide, testing their cytotoxicity and analyses of biodistribution in SCID mice bearing MDA-MB231 tumor.

The method of Fe3O4 magnetic nanoparticle synthesis by co-precipitation, modification by 3-aminopropylsilane and conjugation with pH-(low)-insertion peptide (pHLIP) is reported. The characterization of nanoparticles by scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, elemental and thermogravimetric analyses as well as dynamic light scattering and z-potential measurements is provided. The effect of nanoparticles on the viability of mouse and human peripheral blood mononuclear cells is tested by flow cytometry. The experimental details of nanoparticle administration to tumor-bearing mice, magnetic resonance imaging scanning as well as subsequent tumor sample collection and their processing for transmission electron microscopy, inductively coupled plasma atomic emission spectroscopy, histological and immunohistochemical analyses are described. Biodistribution of the nanoparticles in mice and blood serum analysis data for experimental animals are given. The data are useful for an experiment workflow design and for the development of theranostic systems based on magnetic nanoparticles.

Recruitment of macrophages and bone marrow stem cells to regenerating liver promoted by sodium phthalhydrazide in mice.

Pharmacological interventions which could be hepatoprotective, depending on bioavailability, anti-inflammatory and macrophage-targeting potential of drugs, are still at early preclinical stages. Existing evidence from many animal models of liver injury, as well as from human data, indicate that pharmacological and/or phytochemical interventions have limited impact on liver recovery. Recent studies on stem cell therapies focused on different cell subsets involved in tissue repair, including monocytes/macrophages and bone marrow cells migrating to the injured liver. Partial hepatectomy (PH) resulted in a rapid increase of monocytes/macrophages in bone marrow and liver, which could be further enhanced by prior treatment of animals with sodium phthalhydrazide. Increased number of proliferating Ki67+ hepatocytes, increased total protein and albumin content in regenerating liver, recruitment of CD172a+ macrophages and more differentiated CD45lowCD117+ bone marrow cells, could be further promoted by the treatment of animals with 2 mg/kg b.w. phthalhydrazide, considered immunomodulatory, antioxidant and macrophage-silencing. Phenotypic polarization of macrophages can possibly explain the macrophage reparative capacities, protective against liver injury. Enhanced macrophage cell recruitment from bone marrow to regenerating liver can be possibly one of important events in hepatic recovery.

PMIDA-Modified Fe3O4 Magnetic Nanoparticles: Synthesis and Application for Liver MRI.

The surface modification of Fe3O4-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 °C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r2 and r1 were 341 and 102 mmol-1 s-1, respectively. The possibility of using colloidal solutions of PMIDA-modified MNPs as a T2 contrast agent for liver studies in vivo (at a dose of 0.6 mg kg-1) was demonstrated for the first time.