The assembly state between magnetic nanosensors and their targets orchestrates their magnetic relaxation response

The target-induced clustering of magnetic nanoparticles is typically used for the identification of clinically relevant targets and events. A decrease in the water proton transverse NMR relaxation time, or T(2), is observed upon clustering, allowing the sensitive and accurate detection of target molecules. We have discovered a new mechanistically unique nanoparticle-target interaction resulting in a T(2) increase and demonstrate herein that this increase, and its associated r(2) relaxivity decrease, are also observed upon the interaction of the nanoparticles with ligands or molecular entities. Small molecules, proteins, and a 15-bp nucleic acid sequence were chemically conjugated to polyacrylic-acid-coated iron oxide nanoparticles, and all decreased the original nanoparticle r(2) value. Further experiments established that the r(2) decrease was inversely proportional to the number of ligands bound to the nanoparticle and the molecular weight of the bound ligand. Additional experiments revealed that the T(2)-increasing mechanism was kinetically faster than the conventional clustering mechanism. Most importantly, under conditions that result in T(2) increases, as little as 5.3 fmol of Bacillus anthracis plasmid DNA (pX01 and pX02), 8 pmol of the cholera toxin B subunit (Ctb), and even a few cancer cells in blood were detected. Transition from the binding to the clustering mechanism was observed in the carbohydrate-, Ctb-, and DNA-sensing systems, simply by increasing the target concentration significantly above the nanoparticle concentration, or using Ctb in its pentameric form as opposed to its monomer. Collectively, these results demonstrate that the molecular architectures resulting from the interaction between magnetic nanosensors and their targets directly govern water proton NMR relaxation. We attribute the observed T(2) increases to the bound target molecules partially obstructing the diffusion of solvent water molecules through the superparamagnetic iron oxide nanoparticles' outer relaxation spheres. Finally, we anticipate that this novel interaction can be incorporated into new clinical and field detection applications, due to its faster kinetics relative to the conventional nanoparticle-clustering assays.     

Wash-free magnetic oligonucleotide probes-based NMR sensor for detecting the Hg ion

An easily applied and sensitive sensor for the detection of heavy metal ion residues based entirely on magnetic nanoparticle and oligonucleotide was developed. The tool is established on the relaxation of magnetic nanoparticles with different dispersion states. The target analyte, Hg ions, induce the aggregation of the MNP oligonucleotide probes. Accordingly, the light produced by the magnetic relaxation image and the transverse relaxation time (T(2)) all change due to the effect of the aggregation. The limit of qualitative detection of the sensor is 0.15 ppt. The recoveries from test samples range between 97.1-101.8%. Using the nuclear resonance instrument, the method is a high throughput and sensitive sensor.     

Gd‐DTPA‐Dopamine‐Bisphytanyl Amphiphile: Synthesis,Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents

Here, a new amphiphilic magnetic resonance imaging (MRI) contrast agent, a Gd^III‐chelated diethylenetriaminepentaacetic acid conjugated to two branched alkyl chains via a dopamine spacer, Gd‐DTPA‐dopamine‐bisphytanyl (Gd‐DTPA‐Dop‐Phy), which is readily capable of self‐assembling into liposomal nanoassemblies upon dispersion in an aqueous solution, is reported. In vitro relaxivities of the dispersions were found to be much higher than Magnevist, a commercially available contrast agent, at 0.47 T but comparable at 9.40 T. Analysis of variable temperature ¹⁷O NMR transverse relaxation measurements revealed the water exchange of the nanoassemblies to be faster than that previously reported for paramagnetic liposomes. Molecular reorientation dynamics were probed by ¹H NMRD profiles using a classical inner and outer sphere relaxation model and a Lipari–Szabo “model‐free” approach. High payloads of Gd^III ions in the liposomal nanoassemblies made solely from the Gd‐DTPA‐Dop‐Phy amphiphiles, in combination with slow molecular reorientation and fast water exchange makes this novel amphiphile a suitable candidate to be investigated as an advanced MRI contrast agent.     

Ultrasmall water-soluble metal-iron oxide nanoparticles as T1-weighted contrast agents for magnetic resonance imaging

Using an improved hydrolysis method of inorganic salts assisted with water-bath incubation, ultrasmall water-soluble metal-iron oxide nanoparticles (including Fe(3)O(4), ZnFe(2)O(4) and NiFe(2)O(4) nanoparticles) were synthesized in aqueous solutions, which were used as T(1)-weighted contrast agents for magnetic resonance imaging (MRI). The morphology, structure, MRI relaxation properties and cytotoxicity of the as-prepared metal-iron oxide nanoparticles were characterized, respectively. The results showed that the average sizes of nanoparticles were about 4 nm, 4 nm and 5 nm for Fe(3)O(4), ZnFe(2)O(4) and NiFe(2)O(4) nanoparticles, respectively. Moreover, the nanoparticles have good water dispersibility and low cytotoxicity. The MRI test showed the strong T(1)-weighted, but the weak T(2)-weighted MRI performance of metal-iron oxide nanoparticles. The high T(1)-weighted MRI performance can be attributed to the ultrasmall size of metal-iron oxide nanoparticles. Therefore, the as-prepared metal-iron oxide nanoparticles with good water dispersibility and ultrasmall size can have potential applications as T(1)-weighted contrast agent materials for MRI.     

Synthesis and magnetic relaxation properties of a porous glass magnetic microcarrier

The reaction of formation of magnetic iron oxide nanoparticles from aqueous solutions of Fe(+2,+3) salts was studied under homo- and heterophase conditions of capillary-porous bodies by the nuclear magnetic resonance relaxometry method. Magnetic composites based on Bio-Glas porous glasses were obtained by precipitation of iron oxide nanoparticles in pores ranging in size from 50 to 250 nm. The magnetic relaxation rate of water protons during the heterophase precipitation reaction was examined.     

An NMR-relaxation study of the effect of albumin on aggregation of magnetic iron oxide nanoparticles

The dependence of the aggregation of magnetic iron oxide nanoparticles in aqueous suspensions under the action of human serum albumin is analyzed based on the data of proton magnetic relaxation. It is shown that albumin adsorption on magnetic nanoparticles gives rise to the formation of a protein corona and clusters of magnetic nanoparticles, decreasing the aggregation stability of the suspension in a 7.1-T magnetic field. Clustering of magnetic iron oxide nanoparticles enhances the relaxation efficiency of magnetic suspensions during NMR measurements.     

Comparison of the magnetic properties of metastable hexagonal close-packed Ni nanoparticles with those of the stable face-centered cubic Ni nanoparticles

We report the first magnetic study of pure and metastable hexagonal close-packed (hcp) Ni nanoparticles (sample 1). We also produced stable face-centered cubic (fcc) Ni nanoparticles, as mixtures with the hcp Ni nanoparticles (samples 2 and 3). We compared the magnetic properties of the hcp Ni nanoparticles with those of the fcc Ni nanoparticles by observing the evolution of magnetic properties from those of the hcp Ni nanoparticles to those of the fcc Ni nanoparticles as the number of fcc Ni nanoparticles increased from sample 1 to sample 3. The blocking temperature (T(B)) of the hcp Ni nanoparticles is approximately 12 K for particle diameters ranging between 8.5 and 18 nm, whereas those of the fcc Ni nanoparticles are 250 and 270 K for average particle diameters of 18 and 26 nm, respectively. The hcp Ni nanoparticles seem to be antiferromagnetic for T < T(B) and paramagnetic for T > T(B). This is very different from the fcc Ni nanoparticles, which are ferromagnetic for T < T(B) and superparamagnetic for T > T(B). This unusual magnetic state of the metastable hcp Ni nanoparticles is likely related to their increased bond distance (2.665 angstroms), compared to that (2.499 angstroms) of the stable fcc Ni nanoparticles.     

NMR studies into colloidal stability and magnetic order in fatty acid stabilised aqueous magnetic fluids

We report the physico-chemical characterisation of fatty acid stabilised aqueous magnetic fluids, which are ideal systems for studying the influence of nanoparticle aggregation on the emergent magnetic resonance properties of the suspensions. Stable colloids of superparamagnetic magnetite, Fe(3)O(4), nanoparticle clusters in the 80 to 100 nm size range were produced by in situ nanoparticle growth and stabilisation, and by suspending pre-formed nanoparticles. NMR relaxation analysis shows that the magnetic resonance properties of the two types of suspension differ substantially and provides new insights into how the relaxation mechanisms are determined by the organisation of the nanoparticles within the clusters.     

Sub-100 nm confinement of magnetic nanoparticles using localized magnetic field gradients

Ferromagnetic rods containing thin sections of diamagnetic metal create intense magnetic field gradients that attract and confine magnetic nanoparticles to regions of space as small as 20 nm. The rods (80 nm diameter) comprised alternating sections of CoNi ( approximately 350 nm) and Au (20-160 nm) formed by electrodeposition into porous polycarbonate membranes. Upon magnetizing the rods, large magnetic gradients (106-107 T/m) form at the boundaries between ferromagnetic and diamagnetic sections. These gradients attract and confine magnetic nanoparticles to attoliter volumes of space surrounding the rod. This method provides a new tool for generating intense, highly localized magnetic field gradients, by design, and confining magnetic nanoparticles in these gradients.     

Nuclear magnetic relaxation in water revisited

In this study, we revisited nuclear magnetic relaxation of (1)H in water at very low Larmor frequencies that has been studied intensively in earlier years. We make use of the recently developed superconducting quantum interference device based ultra-low field NMR technique, which enables much easier access to the longitudinal spin-lattice relaxation time T(1) and the transversal spin-spin relaxation time T(2) below several kHz than traditional field cycling methods. Our data reproduce and complement the earlier results, in that they corroborate the finding of an exchange process with a correlation time of about 0.34 ms at room temperature which can be attributed to the migration of hydronium and hydroxyl ions in neutral water via hydrogen bridges. The corresponding relaxation process is driven by the interaction of the protons with (17)O and contributes to the T(1) and the T(2) relaxation rate by about 0.12 s(-1). In addition, we found evidence of a very slow exchange process at about 100 Hz that has hitherto not been reported.     

Intracellular spatial control of fluorescent magnetic nanoparticles

We report a facile intracellular manipulation of fluorescent magnetic Fe3O4-CdSe nanoparticles using magnetic force. The growth of CdSe quantum dots on Fe3O4 nanoparticles produces Fe3O4-CdSe nanoparticles with two distinct properties, fluorescence and superparamagnetism. After nonspecific surface modification using glutathione (GSH), the hydrophilic Fe3O4-CdSe@GSH nanoparticles can be easily uptaken by an HEK293T cell line. Confocal images indicate that the uptaken nanoparticles can be manipulated using a small magnet. The successful intracellular manipulation of magnetic nanoparticles may offer a new strategy for studying polarized cells.     

Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells

Mesoporous silica-coated hollow manganese oxide (HMnO@mSiO(2)) nanoparticles were developed as a novel T(1) magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanoparticle shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R(1)) relaxation enhancement of water protons, which value was measured to be 0.99 (mM(-1)s(-1)) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T(1) values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T(1)-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO(2)-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanoparticles may extend the arsenal of currently available nanoparticle MR contrast agents by providing positive contrast on T(1)-weighted images at high magnetic field strengths.     

Multi-reservoir device for detecting a soluble cancer biomarker

By combining the sensing capabilities of nanoscale magnetic relaxation switches (MRS) within multi-reservoir structures, a potentially powerful implantable multiplexed sensor has been developed. MRS are magnetic nanoparticles that decrease the transverse relaxation time (T(2)) of water in the presence of an analyte. The switches encased in polydimethylsiloxane (PDMS) devices with polycarbonate membranes (10 nm pores) have demonstrated in vitro sensing of the beta subunit of human chorionic gonadotrophin (hCG-beta), which is elevated in testicular and ovarian cancer. Devices showed transverse relaxation time (T(2)) shortening by magnetic resonance imaging (MRI) when incubated in analyte solutions of 0.5 to 5 microg hCG-beta mL(-1). The decrease in T(2) was between 9% and 27% (compared to control devices) after approximately 28 h. This prototype device is an important first step in developing an implantable sensor for detecting soluble cancer biomarkers in vivo.     

Differential magnetic catch and release: experimental parameters for controlled separation of magnetic nanoparticles

Differential magnetic catch and release (DMCR) has been used as a method for the purification and separation of magnetic nanoparticles. DMCR separates nanoparticles in the mobile phase by magnetic trapping of magnetic nanoparticles against the wall of an open tubular capillary wrapped between two narrowly spaced electromagnetic poles. Using Au and CoFe(2)O(4) nanoparticles as model systems, the loading capacity of the 250 μm diameter capillary is determined to be ～130 μg, and is scalable to higher quantities with larger bore capillary. Peak resolution in DMCR is externally controlled by selection of the release time (R(t)) at which the magnetic flux density is removed, however, longer capture times are shown to reduce the capture yield. In addition, the magnetic nanoparticle capture yields are observed to depend on the nanoparticle diameter, mobile phase viscosity and velocity, and applied magnetic flux. Using these optimized parameters, three samples of CoFe(2)O(4) nanoparticles whose diameters are different by less than 10 nm are separated with excellent resolution and capture yield, demonstrating the capability of DMCR for separation and purification of magnetic nanoparticles.     

Solution-state dynamic nuclear polarization at high magnetic field

The goal of dynamic nuclear polarization (DNP) is to enhance NMR signals by transferring electron spin polarization to the nuclei. Although mechanisms such as the solid effect and thermal mixing can be used for DNP in the solid state, currently, the only practical mechanism in solutions is the Overhauser effect (OE), which usually arises due to dipolar relaxation between electrons and the nuclei. At magnetic fields greater than approximately 1 T, dipolar relaxation does not result in a useful enhancement and therefore the conventional wisdom is that DNP should not work in solutions at high magnetic fields. However, scalar relaxation due to time-dependent scalar couplings has a different magnetic field dependence and can lead to substantial OE enhancements. At room temperature and at a magnetic field of 5 T (211 MHz for protons, 140 GHz for electrons), we have observed that scalar relaxation between electrons and nuclei results in NMR signal enhancements of 180, 42, -36, and 8, for 31P, 13C, 15N, and 19F, respectively.     

Metal Nano Networks by Potential-Controlled In Situ Assembling of Gold/Silver Nanoparticles

Non-spherical Au/Ag nanoparticles can be generated by chemical reduction of silver ions in the presence of preformed gold nanoparticles. The process of particle formation can be controlled by concentrations of ligands and reducing agent. The formation of ellipsoidal, nanorod- and peanut-shaped nanoparticles as well as of more complex fractal nanoassemblies can be explained by changes in particle surface state, electrochemical potential formation and particle-internal self-polarization effects. It is possible to create highly fractal nanoassemblies with sizes between the mid-nanometer and the lower micrometer range. The assemblies are marked by high optical absorption and complex nano-networks of very high surface-to-volume ratios and a granular base structure.     

Rational strategy of magnetic relaxation switches for glycoprotein sensing

A rational strategy of magnetic relaxation switches was proposed here to detect a(1)-acid glycoprotein (AGP), an acute phase a-globulin plasma glycoprotein. The assay was based on the relaxation time change between the aggregation of magnetic nanoparticles with concanavalin A and the redispersion with AGP, which can avoid the prozone effect and improve the detection accuracy. The assay was an easy and efficient method with two mixing steps and one measurement step, showing a detection limit of 0.66 nM in 0~0.3 μg mL(-1) AGP, which was far lower than its normal level in human plasma.     

Cubic versus spherical magnetic nanoparticles: the role of surface anisotropy

The magnetic properties of maghemite (gamma-Fe2O3) cubic and spherical nanoparticles of similar sizes have been experimentally and theoretically studied. The blocking temperature, T(B), of the nanoparticles depends on their shape, with the spherical ones exhibiting larger T(B). Other low temperature properties such as saturation magnetization, coercivity, loop shift or spin canting are rather similar. The experimental effective anisotropy and the Monte Carlo simulations indicate that the different random surface anisotropy of the two morphologies combined with the low magnetocrystalline anisotropy of gamma-Fe2O3 is the origin of these effects.     

Synthesis of cyano-bridged magnetic nanoparticles using room-temperature ionic liquids

A principally new exploit of ionic liquids as an alternative reaction medium in the synthesis of cyano-bridged coordination-polymer nanoparticles is reported. Stable colloid solutions containing nanoparticles of cyano-bridged molecule-based magnets, M)[Fe(CN)6]2/[RMIM][BF4] (M2+=Ni, Cu, Co) and Fe4[Fe(CN)6]3/[RMIM][BF4] (R=1-butyl (BMIM), 1-decyl (DMIM)), were prepared in the corresponding 1-R-3-methylimidazolium tetrafluoroborate [RMIM][BF4], which acts as both a stabilising agent and a solvent. By varying the length of the N-alkyl chain on the imidazolium cation of [RMIM]+ and the temperature, the growing process can be controlled to produce nanoparticles of different sizes. By studying the magnetic properties of frozen colloids it is shown that the relaxation of magnetisation is strongly influenced by interparticle interactions, which leads to the appearance of spin-glass-like dynamics in these systems.     

Controlling the self-assembly structure of magnetic nanoparticles and amphiphilic block-copolymers: from micelles to vesicles

We report how to control the self-assembly of magnetic nanoparticles and a prototypical amphiphilic block-copolymer composed of poly(acrylic acid) and polystyrene (PAA-b-PS). Three distinct structures were obtained by controlling the solvent-nanoparticle and polymer-nanoparticle interactions: (1) polymersomes densely packed with nanoparticles (magneto-polymersomes), (2) core-shell type polymer assemblies where nanoparticles are radially arranged at the interface between the polymer core and the shell (magneto-core shell), and (3) polymer micelles where nanoparticles are homogeneously incorporated (magneto-micelles). Importantly, we show that the incorporation of nanoparticles drastically affects the self-assembly structure of block-copolymers by modifying the relative volume ratio between the hydrophobic block and the hydrophilic block. As a consequence, the self-assembly of micelle-forming block-copolymers typically produces magneto-polymersomes instead of magneto-micelles. On the other hand, vesicle-forming polymers tend to form magneto-micelles due to the solubilization of nanoparticles in polymer assemblies. The nanoparticle-polymer interaction also controls the nanoparticle arrangement in the polymer matrix. In N,N-dimethylformamide (DMF) where PS is not well-solvated, nanoparticles segregate from PS and form unique radial assemblies. In tetrahydrofuran (THF), which is a good solvent for both nanoparticles and PS, nanoparticles are homogeneously distributed in the polymer matrix. Furthermore, we demonstrated that the morphology of nanoparticle-encapsulating polymer assemblies significantly affects their magnetic relaxation properties, emphasizing the importance of the self-assembly structure and nanoparticle arrangement as well as the size of the assemblies.