Monodisperse Superparamagnetic Iron Oxide Nanoparticles Research Articles

GRGDS-conjugated and curcumin-loaded magnetic polymeric nanoparticles for the hyperthermia treatment of glioblastoma cells

Thermally responsive and ligand-mediated drug delivery systems have the potential to improve the treatment of brain tumors, especially, most lethal one, glioblastoma multiform (GBM). Magnetic nanoparticle-mediated hyperthermia becomes one of the most promising alternative therapy for GBM treatment in cases where localized heating and targeted delivery of a therapeutic drug can be achieved on the tumor site. In this study, it is aimed to increase the therapeutic efficiency of multi-functionalized nanoparticles (NPs) in combination with radiofrequency hyperthermia (RF-HT) on GBM cells. For this purpose, firstly, a low-cost and portable home-built RF-HT system suitable for in vitro/in vivo studies was successfully implemented and tested at 13.56 MHz frequency with power up to approximately 400 W. Subsequently, the highly monodispersed superparamagnetic iron oxide nanoparticles (SPIONs), which could interact with the RF magnetic field, were synthesized with the mean particle size of 5.6 ± 0.9 nm. The obtained SPIONs were coated with poly (lactic-co-glycolic acid)-poly (ethylene glycol) di-block copolymer (PLGA-b-PEG). Most of the SPIONs were uniformly distributed in such a well-defined spherical-shaped polymeric NP. Moreover, curcumin (Cur), a potential agent for GBM treatment, was loaded into the magnetic polymeric nanoparticles (m-PNPs) with a loading capacity of 8% (w/w, Cur/NPs) and a mean diameter of Cur-loaded m-PNPs (Cur-m-PNPs) was 142 ± 70 nm. To increase cellular uptake and targeting ability of NPs, glycine-arginine-glycine-aspartic acid-serine (GRGDS) peptide was immobilized on the Cur-m-PNPs and the amount of GRGDS was detected as 37 µg/mg NPs. In vitro cytotoxicity studies revealed that the presence of GRGDS on Cur-m-PNPs (GRGDS-Cur-m-PNPs) improved the cytotoxic efficiency of Cur-m-PNPs by 6-fold in GBM cells for all incubation times (24, 48 and 72 h). Furthermore, NPs with RF treatment exhibited higher antitumor activity than that of NPs without RF on GBM cells. This result may be attributed to the thermal (SPIONs) or non-thermal (cellular membrane) effects or both of them on cells. Overall, this study showed that RF-HT in combination with GRGDS-Cur-m-PNPs could provide a feasible approach to improve GBM treatment.

Modular Assembly of Drug and Monodisperse SPIONs for Superior Magnetic and T2-Imaging Performance.

Development of superparamagnetic iron oxide nanoparticles (SPIONs) based theranostics has suffered due to its self-contradictory requirements on water dispersity and drug loadings. Generally well-dispersed SPIONs have excellent MRI performance but are insensitive to magnetism mediated delivery. Besides, loading hydrophobic drugs also hampers the stability of SPIONs which is critical for their biomedical applications. Considering these aspects, we employed curcumin as a cross-linking agent to facilitate the modular assembly of drug and monodisperse SPIONs (Cur/ALN-β-CD-SPIONs). Interestingly, the saturation magnetization of Cur/ALN-β-CD-SPIONs is higher than that of ALN-β-CD-SPIONs, and the value of r2 indicating the negative contrast ability increases to 389.96 mM-1 s-1. Furthermore, the Cur/ALN-β-CD-SPIONs are very stable in PBS buffer over 3 weeks. The mice treated with Cur/ALN-β-CD-SPIONs by tail vein injection displayed a better tumor inhibition effect than that of free curcumin. This study provides a simple method for modular assembly of drug and monodisperse SPIONs, which is crucial to the design of SPIONs with superior T2-imaging performance and drug delivery.

Particle size determination from magnetization curves in reduced graphene oxide decorated with monodispersed superparamagnetic iron oxide nanoparticles

Reduced graphene oxide (RGO) decorated with superparamagnetic iron oxide nanoparticles (SPION) is a novel composite nanomaterial with a myriad of promising applications. However, processes such as the fast and simple synthesis of non-agglomerated monodispersed SPION on RGO and the accurate characterization of particle size distributions remain challenging. Here we present how to solve these two problems. Firstly, we introduce a new microwave-assisted synthesis of stabilized SPION on RGO which is fast, simple and up-scalable but at the same time renders well dispersed SPION with narrow size distributions. The coverage of the RGO flakes with SPION is extensively tuned and the results are compared with a non-stabilized microwave-assisted method. Secondly, we implement an accurate method for the determination of particle size distributions from magnetization curves in RGO-SPION composite nanomaterials. This method is applied to the prepared composites with different particle size distributions, degrees of particle agglomeration and coverage of the RGO flakes. The influence of sample characteristics in the size determination method is discussed and the results are compared with the values obtained from transmission electron microscopy (TEM) and X-ray diffraction (XRD), showing that the method is well suited for these and potentially other types of superparamagnetic composite nanomaterials.

Preparation and In Vitro Cellular Uptake Assessment of Multifunctional Rubik-Like Magnetic Nano-Assemblies.

Through self-assembly of nanoparticles into high-order and stable structures of cubic clusters, high drug-loading rubik-like magnetic nano-assemblies (MNAs), possessing folic acid targeting and strong magnetism-enhanced cellular uptake capabilities, were built. In this study, the core of the cubic drug assemblies consisted of four monodisperse superparamagnetic iron oxide nanoparticles coated with layers of oleic acid (Fe₃O₄@OA), simultaneously encapsulating fluorescein, and Paclitaxol (Flu-MNAs and PTX-MNAs) for imaging and therapeutic applications. To enable preferential tumor cellular uptake by the nanocarriers, the outermost layer of Fe₃O₄ was functionalized with the new dual-oleic acid-polyethylene glycol-folic acid polymer (FA-PEG-Lys-OA₂) as a "shell." The drug carriers exhibited excellent stability and biocompatibility, and showed high drug loading and excellent magnetic response In Vitro. Furthermore, preliminary evaluations of the drug carriers with Hela cells showed effective cellular targeting capability. In addition, the cubic assemblies enhanced anticancer efficiency for Hela cells compared to bare drugs. Especially, the applied external magnetic field further improved the uptake of the vectors, and thereby enhanced the inhibitory effect. In brief, all these results suggested that cubic assemblies could serve as potential strategies for targeted anticancer therapies.

Stealth Nanoparticles Grafted with Dense Polymer Brushes Display Adsorption of Serum Protein Investigated by Isothermal Titration Calorimetry.

Core–shell nanoparticles receive much attention for their current and potential applications in life sciences. Commonly, a dense shell of hydrated polymer, a polymer brush, is grafted to improve colloidal stability of functional nanoparticles and to prevent protein adsorption, aggregation, cell recognition, and uptake. Until recently, it was widely assumed that a polymer brush shell indeed prevents strong association of proteins and that this leads to their superior “stealth” properties in vitro and in vivo. We show using T-dependent isothermal titration calorimetry on well-characterized monodisperse superparamagnetic iron oxide nanoparticles with controlled dense stealth polymer brush shells that “stealth” core–shell nanoparticles display significant attractive exothermic and enthalpic interactions with serum proteins, despite having excellent colloidal stability and negligible nonspecific cell uptake. This observation is at room temperature shown to depend only weakly on variation of iron oxide core diameter and type of grafted stealth polymer: poly(ethylene glycol), poly(ethyl oxazoline), poly(isopropyl oxazoline), and poly(N-isopropyl acrylamide). Polymer brush shells with a critical solution temperature close to body temperature showed a strong temperature dependence in their interactions with proteins with a significant increase in protein binding energy with increased temperature. The stoichiometry of interaction is estimated to be near 1:1 for PEGylated nanoparticles and up to 10:1 for larger thermoresponsive nanoparticles, whereas the average free energy of interaction is enthalpically driven and comparable to a weak hydrogen bond.

Optimization of Magneto-thermally Controlled Release Kinetics by Tuning of Magnetoliposome Composition and Structure

Stealth (PEGylated) liposomes have taken a central role in drug formulation and delivery combining efficient transport with low nonspecific interactions. Controlling rapid release at a certain location and time remains a challenge dependent on environmental factors. We demonstrate a highly efficient and scalable way to produce liposomes of any lipid composition containing homogeneously dispersed monodisperse superparamagnetic iron oxide nanoparticles in the membrane interior. We investigate the effect of lipid composition, particle concentration and magnetic field actuation on colloidal stability, magneto-thermally actuated release and passive release rates. We show that the rate and amount of encapsulated hydrophilic compound released by actuation using alternating magnetic fields can be precisely controlled from stealth liposomes with high membrane melting temperature. Extraordinarily low passive release and temperature sensitivity at body temperature makes this a promising encapsulation and external-trigger-on-demand release system. The introduced feature can be used as an add-on to existing stealth liposome drug delivery technology.

Tunability of Size and Magnetic Moment of Iron Oxide Nanoparticles Synthesized by Forced Hydrolysis

To utilize iron oxide nanoparticles in biomedical applications, a sufficient magnetic moment is crucial. Since this magnetic moment is directly proportional to the size of the superparamagnetic nanoparticles, synthesis methods of superparamagnetic iron oxide nanoparticles with tunable size are desirable. However, most existing protocols are plagued by several drawbacks. Presented here is a one-pot synthesis method resulting in monodisperse superparamagnetic iron oxide nanoparticles with a controllable size and magnetic moment using cost-effective reagents. The obtained nanoparticles were thoroughly characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) measurements. Furthermore, the influence of the size on the magnetic moment of the nanoparticles is analyzed by superconducting quantum interference device (SQUID) magnetometry. To emphasize the potential use in biomedical applications, magnetic heating experiments were performed.

Complete Exchange of the Hydrophobic Dispersant Shell on Monodisperse Superparamagnetic Iron Oxide Nanoparticles.

High-temperature synthesized monodisperse superparamagnetic iron oxide nanoparticles are obtained with a strongly bound ligand shell of oleic acid and its decomposition products. Most applications require a stable presentation of a defined surface chemistry; therefore, the native shell has to be completely exchanged for dispersants with irreversible affinity to the nanoparticle surface. We evaluate by attenuated total reflectance−Fourier transform infrared spectroscopy (ATR−FTIR) and thermogravimetric analysis/differential scanning calorimetry (TGA/DSC) the limitations of commonly used approaches. A mechanism and multiple exchange scheme that attains the goal of complete and irreversible ligand replacement on monodisperse nanoparticles of various sizes is presented. The obtained hydrophobic nanoparticles are ideally suited for magnetically controlled drug delivery and membrane applications and for the investigation of fundamental interfacial properties of ultrasmall core–shell architectures.

Silica-coated super-paramagnetic iron oxide nanoparticles (SPIONPs): a new type contrast agent of T1 magnetic resonance imaging (MRI).

Magnetic resonance imaging (MRI), a sophisticated promising three-dimensional tomographic noninvasive diagnostic technique, has an intrinsic advantage in safety compared with radiotracer and optical imaging modalities; however, MRI contrast agents are less sensitive than complexes used in other imaging techniques. Usually the clinically used Gd-based complexes MRI-T1 contrast agents are toxic; therefore, the demand for nontoxic novel T1-weighted MRI candidates with ultrasensitive imaging and advanced functionality is very high. In this research, silica-coated ultra-small monodispersed super-paramagnetic iron oxide nanoparticles were synthesized via a thermal decomposition method, which demonstrated themselves as a high performance T1-weighted MRI contrast agent for heart, liver, kidney and bladder based on in vivo imaging analyses. Transmission electron microscopy (TEM) results illustrated that the diameter of the SPIONPs was in the range of 4 nm and the average size of Fe3O4@SiO2 was about 30-40 nm. X-ray diffraction (XRD) and Raman spectroscopy analyses revealed the phase purity of the prepared SPIONPs. These magnetite nanoparticles exhibited a weak magnetic moment at room temperature because of the spin-canting effect, which promoted a high positive signal enhancement ability. MTT assays and histological analysis demonstrated good biocompatibility of the SPIONPs in vitro and in vivo. In addition, the silica-coated ultra-small (4 nm sized) magnetite nanoparticles exhibited a good r1 relaxivity of 1.2 mM-1 s-1 and a low r2/r1 ratio of 6.5 mM-1 s-1. In vivo T1-weighted MR imaging of heart, liver, kidney and bladder in mice after intravenous injection of nanoparticles further verified the high sensitivity and biocompatibility of the as-synthesized magnetite nanoparticles. These results reveal silica-coated SPIONPs as a promising candidate for a T1 contrast agent with extraordinary capability to enhance MR images.

Solvothermal synthesis and characterization of monodisperse superparamagnetic iron oxide nanoparticles

Abstract A series of magnetic iron oxide nanoparticle clusters with different structure guide agents were synthesized by a modified solvothermal method and characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), thermogravimetric analyses (TG), a vibrating sample magnetometer (VSM) and Fourier transform infrared spectroscopy (FTIR). It is found that the superparamagnetic nanoparticles guided by NaCit (sodium citrate) have high saturation magnetization ( M s ) of 69.641 emu/g and low retentivity ( M r ) of 0.8 emu/g. Guiding to form superparamagnetic clusters with size range of 80–110 nm, the adherent small-molecule citrate groups on the surface prevent the prefabricated ferrite crystals growing further. In contrast, the primary small crystal guided and stabilized by the PVP long-chain molecules assemble freely to larger ones and stop growing in size range of 100–150 nm, which has saturation magnetization ( M s ) of 97.979 emu/g and retentivity ( M r ) of 46.323 emu/g. The relevant formation mechanisms of the two types of samples are proposed at the end. The superparamagnetic ferrite clusters guided by sodium citrate are expected to be used for movement controlling of passive interference particles to avoid aggregation and the sample guided by PVP will be a candidate of nanometer wave absorbing material.

Effect of PEG molecular weight on stability, T2 contrast, cytotoxicity, and cellular uptake of superparamagnetic iron oxide nanoparticles (SPIONs)

Superparamagnetic iron oxide nanoparticles (SPIONs) are currently unavailable as MRI contrast agents for detecting atherosclerosis in the clinical setting because of either low signal enhancement or safety concerns. Therefore, a new generation of SPIONs with increased circulation time, enhanced image contrast, and less cytotoxicity is essential. In this study, monodisperse SPIONs were synthesized and coated with polyethylene glycol (PEG) of varying molecular weights. The resulting PEGylated SPIONs were characterized, and their interactions with vascular smooth muscle cells (VSMCs) were examined. SPIONs were tested at different concentrations (100 and 500ppm Fe) for stability, T2 contrast, cytotoxicity, and cellular uptake to determine an optimal formulation for in vivo use. We found that at 100ppm Fe, the PEG 2K SPIONs showed adequate stability and magnetic contrast, and exhibited the least cytotoxicity and nonspecific cellular uptake. An increase in cell viability was observed when the SPION-treated cells were washed with PBS after 1h incubation compared to 5 and 24h incubation without washing. Our investigation provides insight into the potential safe application of SPIONs in the clinic.

Monodisperse superparamagnetic nanoparticles by thermolysis of Fe(III) oleate and mandelate complexes

Monodisperse superparamagnetic iron oxide nanoparticles of controlled size were synthesized by thermal decomposition of organic iron compounds in different high-boiling solvents in the presence of oleic acid and/or oleylamine. The compounds included Fe(III) oleate and mandelate, formed from FeCl3 and the respective acids. The size of the nanoparticles was easily tuned to 8–27 nm by varying the experimental conditions. The nanoparticles were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), and magnetization measurements. The hydrophobic coating of the particles was analyzed by thermogravimetric analysis (TGA) and atomic absorption spectroscopy (AAS). To make the particles biocompatible and water dispersible, nontoxic hydrophilic poly(ethylene glycol) derivatives were synthesized and used for phase transfer of hydrophobic particles into water using a ligand-exchange procedure.

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

Superparamagnetic iron oxide nanoparticles (SPIO) can be used to image physiological processes and anatomical, cellular and molecular changes in diseases. The clinical applications range from the imaging of tumors and metastases in the liver, spleen and bone marrow, the imaging of lymph nodes and the CNS, MRA and perfusion imaging to atherosclerotic plaque and thrombosis imaging. New experimental approaches in molecular imaging describe undirected SPIO trapping (passive targeting) in inflammation, tumors and associated macrophages as well as the directed accumulation of SPIO ligands (active targeting) in tumor endothelia and tumor cells, areas of apoptosis, infarction, inflammation and degeneration in cardiovascular and neurological diseases, in atherosclerotic plaques or thrombi. The labeling of stem or immune cells allows the visualization of cell therapies or transplant rejections. The coupling of SPIO to ligands, radio- and/or chemotherapeutics, embedding in carrier systems or activatable smart sensor probes and their externally controlled focusing (physical targeting) enable molecular tumor therapies or the imaging of metabolic and enzymatic processes. Monodisperse SPIO with defined physicochemical and pharmacodynamic properties may improve SPIO-based MRI in the future and as targeted probes in diagnostic magnetic resonance (DMR) using chip-based µNMR may significantly expand the spectrum of in vitro analysis methods for biomarker, pathogens and tumor cells. Magnetic particle imaging (MPI) as a new imaging modality offers new applications for SPIO in cardiovascular, oncological, cellular and molecular diagnostics and therapy.

A Simple and Widely Applicable Method to 59Fe-Radiolabel Monodisperse Superparamagnetic Iron Oxide Nanoparticles for In Vivo Quantification Studies

A simple, fast, efficient, and widely applicable method to radiolabel the cores of monodisperse superparamagnetic iron oxide nanoparticles (SPIOs) with (59)Fe was developed. These cores can be used as precursors for a variety of functionalized nanodevices. A quality control using filtration techniques, size-exclusion chromatography, chemical degradation methods, transmission electron microscopy, and magnetic resonance imaging showed that the nanoparticles were stably labeled with (59)Fe. Furthermore, the particle structure and the magnetic properties of the SPIOs were unchanged. In a second approach, monodisperse SPIOs stabilized with (14)C-oleic acid were synthesized, and the stability of this shell labeling was studied. In proof of principle experiments, the (59)Fe-SPIOs coated with different shells to make them water-soluble were used to evaluate and compare in vivo pharmacokinetic parameters such as blood half-life. It could also be shown that our radiolabeled SPIOs embedded in recombinant lipoproteins can be used to quantify physiological processes in closer detail than hitherto possible. In vitro and in vivo experiments showed that the (59)Fe label is stable enough to be applied in vivo, whereas the (14)C label is rapidly removed from the iron core and is not adequate for in vivo studies. To obtain meaningful results in in vivo experiments, only (59)Fe-labeled SPIOs should be used.

Size-controlled synthesis of monodisperse superparamagnetic iron oxide nanoparticles

Abstractd Monodisperse iron oxide nanoparticles were prepared by thermal decomposition of iron carbonyl in octyl ether in the presence of oleic acid. The particle size could be tuned from 7 nm to 25 nm. The dual role of oleic acid as a surfactant and a boiling-point elevating agent was discussed. The impacts of varied reflux conditions were investigated and a new monodisperse mechanism was given. High-resolution transmission electron microscopy (HRTEM) and selected area electron diffraction (SAED) were used to study the oxidation states of iron oxide nanoparticles. The evolution of d -spacing values in HRTEM images and SAED patterns demonstrated the transition from γ-Fe 2 O 3 to Fe 3 O 4 with the increasing particle size. Superconducting quantum interference device (SQUID) and vibrating sample magnetometer (VSM) were used to reveal the superparamagnetic behavior of as-synthesized nanoparticles.

Complete separation of magnetic nanoparticlesvia chemical cleavage of dextran by ethylenediamine for intracellular uptake

Completely water dispersible and highly monodispersed superparamagnetic iron oxide nanoparticles (SPIONs) were prepared. The surface of SPIONs was modified with dual-crosslinked amine activated dextran (AMD) and chemical cleavage of AMD on SPIONs was carried out by ethylenediamine hydrochloride (EDA). Transmission electron microscopy (TEM) revealed that individual SPIONs were completely separated in water and the average diameter of resulting nanoparticles was 4.4 nm.

Preparation of Water-Dispersible and Biocompatible Iron Oxide Nanoparticles for MRI Agent

Highly monodisperse superparamagnetic iron oxide nanoparticles (SPIONs, 7.5 nm gamma- F <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> O <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> ) were synthesized by thermal decomposition of iron pentacarbonyl and consecutive aeration in organic medium. By treating with a small amount of iron pentacarbonyl, Fe-rich surface has been formed on SPION. Water-dispersible SPIONs (SPION-MPA) were prepared by Fe-S covalent conjugation between Fe-rich SPION and mercaptopropionic acid (MPA) and then, transformed to SPION-MPA-dextran composite by physical adsorption of biocompatible polymer dextran. The hydrodynamic diameter of SPION-MPA-dextran was in the range of 225~237 nm in water. MR contrast and spin-spin relaxation intensity of our SPION-MPA-dextran were similar to those of the commercial products, Ferridex and Resovist.

Surface modification of hydrophobic iron oxide nanoparticles for clinical applications

Monodisperse superparamagnetic iron oxide nanoparticles (SPIONs) were prepared by thermal decomposition of Fe(CO)/sub 5/ and by consecutive aeration in organic medium. The resultant hydrophobic SPION surface was modified to be hydrophilic via Fe-S covalent bond with bi-functional 3-mercaptopropionic acid and then, the terminal carboxylic acid group was esterified with dextran for biocompatibility. Analysis by water dispersity, transmission electron microscopy, X-ray diffraction, and Fourier transformed infrared spectroscopy are reported.