Superparamagnetic Iron Oxide Nanoparticles Core Research Articles

Development of novel poly-l-lysine-modified sericin-coated superparamagnetic iron oxide nanoparticles as siRNA carrier

Small interfering RNA (siRNA) is a promising therapeutic modality, however, its successful clinical application is still challenging due to the lack of safe and efficient carrier systems. Superparamagnetic iron oxide nanoparticles (SPIONs)-based drug or gene carrier systems have displayed tremendous promise in nanomedicine. They possess intrinsic unique superparamagnetism that provides them to be concentrated in the targeted therapeutic site of action where an external magnetic field is applied. SPIONs can be also designed as theranostic agents to achieve simultaneous therapeutic and diagnostic purposes. Despite these favorable features, SPIONs are colloidally unstable and can be easily eliminated in the circulation. More importantly, the toxicological concerns associated with SPIONs, which often lead to the generation of reactive oxygen species (ROS), need to be thoroughly considered. Various types of polymers have been proposed so far to cover the surface of SPION to overcome these disadvantages. Silk protein, sericin can be ideal as a coating material due to its high biocompatibility, good biodegradability, and in vivo stability. In terms of the development of SPIONs as siRNA carriers, to the best of our knowledge, no protein was used as the coating material, and SPIONs coated with sericin have not been reported in the literature as a drug or gene carrier system. The present study aimed to design and develop a novel siRNA carrier system based on SPIONs. We prepared and characterized a nanomaterial comprised of SPIONs covalently coated with a biocompatible protein, sericin (Ser), and modified with a cationic polymer, poly- l -lysine (PLL) to incorporate the negatively charged siRNA. Transmission electron microscopy (TEM) images revealed that obtained nanoparticles had narrow size distribution with spherical shape and coated nanoparticles presented black spheres in the SPION core surrounded with a gray layer, which indicated sericin coating. Adding PLL to Ser-SPIONs did not cause any dramatic change in nanoparticle size whereas it provided a net positive charge to the particles. Additionally, electron spin resonance (ESR) analysis showed that sericin coating and PLL modification did not efface the superparamagnetic properties of the particles. We successfully attached the control-siRNAs to the surface of PLL/Ser-SPIONs, forming siRNA-PLL/Ser-SPION nanoplatforms and achieving high siRNA binding efficiencies ranged between 81.90% and 93.50%. The ability of SPIONs-based nanocarriers to fulfill their promises in clinical use depends on keeping their nanotoxicity properties to a minimum. All the nanoparticle formulations tested herein were found to be biocompatible against non-cancerous and cancer cells by cytotoxicity assays. We also investigated the effect of resulting bare particles, PLL/Ser-SPIONs, on the clonogenicity of cancer cells. According to the results, the cells exhibited colony formation ability depending on the concentration of the nanoparticles and PLL/Ser-SPIONs did not block clonogenicity, except at very high doses. Taken together, our findings imply that these new PLL/Ser-SPIONs can be considered as a safe and promising carrier candidate to be used and developed for further siRNA-based applications. • A new siRNA nanocarrier system composed of SPIONs coated with sericin, and modified with PLL was successfully synthesized.. • High siRNA binding efficiency was achieved by incorporating the siRNA with the PLL/Ser-SPIONs. • siRNA loaded PLL/Ser-SPIONs exhibited sustained in vitro siRNA release kinetics. • Cytotoxicity and colony formation assays revealed that PLL/Ser-SPIONs were biocompatible and safe materials. • Our work suggests that PLL/Ser-SPIONs can be a promising siRNA carrier candidate for gene silencing therapies.

Assessment of Superparamagnetic Iron Oxide Nanoparticle Poly(Ethylene Glycol) Coatings on Magnetic Resonance Relaxation for Early Disease Detection

Objective: Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are widely researched as contrast agents in clinical magnetic resonance imaging (MRI). SPIONs are frequently coated with anti-biofouling substances such as poly(ethylene glycol) (PEG) to prevent protein deposition and improve circulation time in vivo. The aim of this study is to optimize SPION MR properties with respect to physicochemical properties of the core SPION and the polymeric coating to better understand the interaction of these parameters and the efficacy of the designed agent. Methods: We used different methods of chemical attachment of a polymer, polymer chain length, and polymer coating density and examined their effects on the MR relaxivities of SPIONs. Results: These studies indicate that the chemical composition and, in particular, the hydrophobicity/hydrophilicity of the chemical group linking PEG chains to a SPION core may play a larger role in the resulting MR relaxivities than other variable properties such as SPION core size and PEG chain length. Conclusions: The method of SPION fabrication and chemical composition of the coating play a significant role in the MR relaxivities of the resulting particles. These results should be considered in the fabrication of particles for clinical purposes, particularly when optimization of the MR relaxivities is desired.

Functional Magnetic Core-Shell System-Based Iron Oxide Nanoparticle Coated with Biocompatible Copolymer for Anticancer Drug Delivery.

Polymer coating has drawn increasing attention as a leading strategy to overcome the drawbacks of superparamagnetic iron oxide nanoparticles (SPIONs) in targeted delivery of anticancer drugs. In this study, SPIONs were modified with heparin-Poloxamer (HP) shell to form a SPION@HP core-shell system for anticancer drug delivery. The obtained formulation was characterized by techniques including transmission electron microscopy (TEM), Fourier transform infrared spectra (FT-IR), vibration sample magnetometer (VSM), proton nuclear magnetic resonance (1H-NMR), and powder X-ray diffraction (XRD). Results showed the successful attachment of HP shell on the surface of SPION core and the inability to cause considerable effects to the crystal structure and unique magnetic nature of SPION. The core-shell system maintains the morphological features of SPIONs and the desired size range. Notably, Doxorubicin (DOX), an anticancer drug, was effectively entrapped into the polymeric shell of SPION@HP, showing a loading efficiency of 66.9 ± 2.7% and controlled release up to 120 h without any initial burst effect. Additionally, MTT assay revealed that DOX-loaded SPION@HP exerted great anticancer effect against HeLa cells and could be safely used. These results pave the way for the application of SPION@HP as an effective targeted delivery system for cancer treatment.

New Magneto-Fluorescent Hybrid Polymer Nanogel for Theranostic Applications.

Herein we have reported a new magneto-fluorescent nanogel built on photoluminescent comacromer [PEG-maleic acid-glycine], N,N-dimethyl aminoethylmethacrylate and citrate-capped superparamagnetic iron oxide nanoparticles (SPION). The nanogel was found to have core-shell morphology (SPION core and PEG shell) with particle size around 80 nm. The cytocompatibility of the synthesized nanogel was studied using MTT, live/dead assays, and flow cytometry. The cellular uptake of the nanogel on cervical cancer cell line Hela evaluated through Prussian blue staining and fluorescence microscopy has revealed good cancer cell imaging capability. Magnetic hyperthermia experiments have shown that the synthesized nanogel caused the lysis of cancer cells. The fluorescence bioimaging capability of the nanogel in the murine model has shown good near IR imaging capability. Overall, the reported results suggest that the magneto-fluorescent nanogel shows promising future potential for cancer theranostic applications.

Luteinizing hormone-releasing hormone targeted superparamagnetic gold nanoshells for a combination therapy of hyperthermia and controlled drug delivery

In this, we developed superparamagnetic iron oxide nanoparticles (SPIONs) to be appropriate for the diagnosis and treatment of cancer cells by means of magnetic resonance imaging (MRI) and magnetically controlled hyperthermia/drug delivery (respectively). For the preparation of composite, we started with SPIONs, followed by its coating with gold to form SPIONs@Au, which further conjugated with luteinizing hormone-releasing hormone (LHRH) protein by making use of the cysteamine (Cyst) space linker and finally loaded with 5-Fluororacil (5-Fu) anticancer drug to form SPIONs@Au-Cyst-LHRH_5-Fu composite. Thus formed composite was thoroughly characterized by making use of the instrumental analysis such as HRTEM, EDAX, DLS, TGA, XPS, UV–vis, FTIR, HPLC and SQUID magnetics. We found from the analysis that the particles are spherical in shape, monodispersed with a size distribution of around 6.9nm in powdered dry form, while in solution phase it is 8.7nm. The UV–vis, FTIR, and HPLC studies confirmed for the loading of the 5-Fu drug onto the surface of SPIONs core and the maximum amount of drug that got adsorbed to be about 42%. The SQUID magnetic studies provided the information for the superparamagnetic behavior of the drug loaded SPIONs and the saturation magnetization (Ms) values observed to be about 11emu/g and the blocking temperature (TB) of 348K. On testing the particles to see the effects of magnetic fluid hyperthermia (MFH) due to some changes in the solvent medium and oscillating frequency, the material seems to be highly active in aqueous medium and the activity gets increased with respect to the applied frequency of oscillation (430Hz>230Hz>44Hz). From the heat release studies, the calculated specific power loss (SPL) values for the SPIONs@Au-Cyst-LHRH_5-Fu composite are at the highest of 1068W/g in water (430Hz) vs the least of 68W/g in toluene (44Hz). Further, the drug release studies tested under the influence of magnetic field provided the information that the composite released its entire loaded drug following an exposure to the magnetic field (430Hz over 4h time), while only 53% (over 5h) for the controlled measurements of no magnetic field, thereby supporting to have the magnetic field so as to observe the externally controlled drug release effects. Finally, the results of the study provide the information that the SPIONs@Au-Cyst-LHRH_5-Fu composite can be potential for theranostic applications of cancer through the phenomenon of applying for MRI, magnetically controlled hyperthermia and drug delivery externally.

Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting.

The low therapeutic index of conventional chemotherapy and poor prognosis of patients diagnosed with metastatic cancers are prompting clinicians to adopt newer strategies to simultaneously detect cancer lesions at an early stage and to precisely deliver anticancer drugs to tumor sites. In this study, we employed a novel strategy to engineer a polyvalent theranostic nanocarrier consisting of superparamagnetic iron oxide nanoparticle core (SPIONs) decorated with folic acid-polyamidoamine dendrimers surface (FA-PAMAM). In addition, a highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin (CDF) was coloaded in the FA-PAMAM dendrimer to increase its solubility and assess its therapeutic potentials. The resulting targeted nanoparticles (SPIONs@FA-PAMAM-CDF) exhibited high MR contrast. When tested on folate receptor overexpressing ovarian (SKOV3) and cervical (HeLa) cancer cells, the CDF loaded targeted nanoformulations showed higher accumulation with a better anticancer activity as compared to the nontargeted counterparts, possibly due to multivalent folate receptor binding interaction with cells overexpressing the target. The results were corroborated by observation of a larger population of cells undergoing apoptosis due to upregulation of tumor suppressor phosphatase and tensis homologue (PTEN), caspase 3, and inhibition of NF-κB in groups treated with the targeted formulations, which further confirmed the ability of the multivalent theranostic nanoparticles for simultaneous imaging and therapy of cancers.

Synthesis of Cationized Magnetoferritin for Ultra-fast Magnetization of Cells.

Many important biomedical applications, such as cell imaging and remote manipulation, can be achieved by labeling cells with superparamagnetic iron oxide nanoparticles (SPIONs). Achieving sufficient cellular uptake of SPIONs is a challenge that has traditionally been met by exposing cells to elevated concentrations of SPIONs or by prolonging exposure times (up to 72 hr). However, these strategies are likely to mediate toxicity. Here, we present the synthesis of the protein-based SPION magnetoferritin as well as a facile surface functionalization protocol that enables rapid cell magnetization using low exposure concentrations. The SPION core of magnetoferritin consists of cobalt-doped iron oxide with an average particle diameter of 8.2 nm mineralized inside the cavity of horse spleen apo-ferritin. Chemical cationization of magnetoferritin produced a novel, highly membrane-active SPION that magnetized human mesenchymal stem cells (hMSCs) using incubation times as short as one minute and iron concentrations as lows as 0.2 mM.

Synthesis of Cationized Magnetoferritin for Ultra-fast Magnetization of Cells

Many important biomedical applications, such as cell imaging and remote manipulation, can be achieved by labeling cells with superparamagnetic iron oxide nanoparticles (SPIONs). Achieving sufficient cellular uptake of SPIONs is a challenge that has traditionally been met by exposing cells to elevated concentrations of SPIONs or by prolonging exposure times (up to 72 hr). However, these strategies are likely to mediate toxicity. Here, we present the synthesis of the protein-based SPION magnetoferritin as well as a facile surface functionalization protocol that enables rapid cell magnetization using low exposure concentrations. The SPION core of magnetoferritin consists of cobalt-doped iron oxide with an average particle diameter of 8.2 nm mineralized inside the cavity of horse spleen apo-ferritin. Chemical cationization of magnetoferritin produced a novel, highly membrane-active SPION that magnetized human mesenchymal stem cells (hMSCs) using incubation times as short as one minute and iron concentrations as lows as 0.2 mM.

Co-precipitation of DEAE-dextran coated SPIONs: how synthesis conditions affect particle properties, stem cell labelling and MR contrast.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as contrast agents for stem cell tracking using magnetic resonance imaging (MRI). The total mass of iron oxide that can be internalised into cells without altering their viability or phenotype is an important criterion for the generation of contrast, with SPIONs designed for efficient labelling of stem cells allowing for an increased sensitivity of detection. Although changes in the ratio of polymer and iron salts in co-precipitation reactions are known to affect the physicochemical properties of SPIONs, particularly core size, the effects of these synthesis conditions on stem cell labelling and magnetic resonance (MR) contrast have not been established. Here, we synthesised a series of cationic SPIONs with very similar hydrodynamic diameters and surface charges, but different polymer content. We have investigated how the amount of polymer in the co-precipitation reaction affects core size and modulates not only the magnetic properties of the SPIONs but also their uptake into stem cells. SPIONs with the largest core size and lowest polymer content presented the highest magnetisation and relaxivity. These particles also had the greatest uptake efficiency without any deleterious effect on either the viability or function of the stem cells. However, for all particles internalised in cells, the T2 and T2* relaxivity was independent of the SPION's core size. Our results indicate that the relative mass of iron taken up by cells is the major determinant of MR contrast generation and suggest that the extent of SPION uptake can be regulated by the amount of polymer used in co-precipitation reactions. Copyright © 2016 John Wiley & Sons, Ltd.

Magnetic and dendritic catalysts.

The recovery and reuse of catalysts is a major challenge in the development of sustainable chemical processes. Two methods at the frontier between homogeneous and heterogeneous catalysis have recently emerged for addressing this problem: loading the catalyst onto a dendrimer or onto a magnetic nanoparticle. In this Account, we describe representative examples of these two methods, primarily from our research group, and compare them. We then describe new chemistry that combines the benefits of these two methods of catalysis. Classic dendritic catalysis has involved either attaching the catalyst covalently at the branch termini or within the dendrimer core. We have used chelating pyridyltriazole ligands to insolubilize catalysts at the termini of dendrimers, providing an efficient, recyclable heterogeneous catalysts. With the addition of dendritic unimolecular micelles olefin metathesis reactions catalyzed by commercial Grubbs-type ruthenium-benzylidene complexes in water required unusually low amounts of catalyst. When such dendritic micelles include intradendritic ligands, both the micellar effect and ligand acceleration promote faster catalysis in water. With these types of catalysts, we could carry out azide alkyne cycloaddition ("click") chemistry with only ppm amounts of CuSO4·5H2O and sodium ascorbate under ambient conditions. Alternatively we can attach catalysts to the surface of superparamagnetic iron oxide nanoparticles (SPIONs), essentially magnetite (Fe3O4) or maghemite (γ-Fe2O3), offering the opportunity to recover the catalysts using magnets. Taking advantage of the merits of both of these strategies, we and others have developed a new generation of recyclable catalysts: dendritic magnetically recoverable catalysts. In particular, some of our catalysts with a γ-Fe2O3@SiO2 core and 1,2,3-triazole tethers and loaded with Pd nanoparticles generate strong positive dendritic effects with respect to ligand loading, catalyst loading, catalytic activity and recyclability. In other words, the dendritic catalysts were more efficient and more stable than their nondendritic γ-Fe2O3@SiO2 analogues. The bulk at the dendritic periphery helps to localize the metal nanoparticles at the SPION core surface, which confers these advantages. We could also use sonification as a remarkably simple and efficient method to impregnate the SPIONs with dendrimer-encapsulated PdNPs. Catalysis within the hydrophobic dendrimer pockets that include ligands leads to rapid turnover with or without a γ-Fe2O3@SiO2 core. In addition, catalytically active metal nanoparticles are more robust when they are loaded onto the surface of a γ-Fe2O3@SiO2 dendritic core. Herein, we illustrate this chemistry with examples including olefin metathesis, click chemistry, cross carbon-carbon bond forming reactions, and selective alcohol oxidation.

Photothermal Microscopy of the Core of Dextran-Coated Iron Oxide Nanoparticles During Cell Uptake

A detailed understanding of cellular interactions with superparamagnetic iron oxide nanoparticles (SPIONs) is critical when their biomedical applications are considered. We demonstrate how photothermal microscopy can be used to follow the cellular uptake of SPIONs by direct imaging of the iron oxide core. This offers two important advantages when compared with current strategies employed to image magnetic cores: first, it is nondestructive and is therefore suitable for studies of live cells and, second, it offers a higher sensitivity and resolution, thus allowing for the identification of low levels of SPIONs within a precise subcellular location. We have shown that this technique may be applied to the imaging of both cell monolayers and cryosections. In the former we have demonstrated the role of temperature on the rate of endocytosis, while in the latter we have been able to identify cells labeled with SPIONs from a mixed population containing predominantly unlabeled cells. Direct imaging of the SPION core is of particular relevance for research involving clinically approved SPIONs, which do not contain fluorescent tags and therefore cannot be detected via fluorescence microscopy.

An activatable multimodal/multifunctional nanoprobe for direct imaging of intracellular drug delivery

Multifunctional nanoparticles integrated with imaging modalities (such as magnetic resonance and optical) and therapeutic drugs are promising candidates for future cancer diagnostics and therapy. While targeted drug delivery and imaging of tumor cells have been the major focus in engineering nanoparticle probes, no extensive efforts have been made towards developing sensing probes that can confirm and monitor intracellular drug release events. Here, we present quantum dot (Qdot)-iron oxide (IO) based multimodal/multifunctional nanocomposite probe that is optically and magnetically imageable, targetable and capable of reporting on intracellular drug release events. Specifically, the probe consists of a superparamagnetic iron oxide nanoparticle core (IONP) decorated with satellite CdS:Mn/ZnS Qdots where the Qdots themselves are further functionalized with STAT3 inhibitor (an anti-cancer agent), vitamin folate (as targeting motif) and m-polyethylene glycol (mPEG, a hydrophilic dispersing agent). The Qdot luminescence is quenched in this nanocomposite probe (“OFF” state) due to combined electron/energy transfer mediated quenching processes involving IONP, folate and STAT3 agents. Upon intracellular uptake, the probe is exposed to the cytosolic glutathione (GSH) containing environment resulting in restoration of the Qdot luminescence (“ON” state), which reports on uptake and drug release. Probe functionality was validated using fluorescence and MR measurements as well as in vitro studies using cancer cells that overexpress folate receptors.

From synthetic to natural nanoparticles: monitoring the biodegradation of SPIO (P904) into ferritin by electron microscopy

A strong focus on Superparamagnetic Iron Oxide Nanoparticles (SPIOs) has been appreciated recently especially for their use in Magnetic Resonance Imaging (MRI). However, some questions are being raised over these particles due to their long-term toxicity related to the production of toxic free iron during their biodegradation. Here we show by Electron Microscopy how SPIOs (P904) (Guerbet, Paris) are degraded after they are taken up by macrophages, so that iron from the SPIO core is progressively incorporated into the iron-storing protein ferritin (a nontoxic form of iron).

Fabrication of carboxylic functionalized superparamagnetic mesoporous silica microspheres and their application for removal basic dye pollutants from water

Superparamagnetic mesoporous silica microspheres embedded with a silica-coated superparamagnetic iron oxide nanoparticles core and mesoporous silica shell have been prepared using stearyltrimethyl ammonium bromide (STAB) as surfactant template. The superparamagnetic mesoporous silica microspheres then were modified with anhydride functionalized silane to graft carboxylic groups and developed for removing basic dye pollutants, e.g., Methylene Blue (MB) and Acridine Orange (AO) from wastewaters. The results show that the as-prepared adsorbent exhibits high adsorption capacity, extremely rapid adsorption rate and separation convenience for basic dye pollutants removal. Furthermore, the as-prepared adsorbent can be regenerated by simple washing with acid solution to recover both the adsorbents and the adsorbed dyes. The regenerated adsorbent can be reused for dye removal and the adsorption efficiency is still above 88% even after use for seven times. So it can be used as an economic recyclable tool for dyes pollutants removal from wastewater.

Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery

Ribonucleic acid interference (RNAi) is a powerful molecular tool that has potential to revolutionize the treatment of cancer. One major challenge of applying this technology for clinical application is the lack of site-specific carriers that can effectively deliver short interfering RNA (siRNA) to cancer cells. Here we report the development and assessment of a cancer-cell specific magnetic nanovector construct for efficient siRNA delivery and non-invasive monitoring through magnetic resonance imaging (MRI). The base of the nanovector construct is comprised of a superparamagnetic iron oxide nanoparticle core coated with polyethylene glycol (PEG)-grafted chitosan, and polyethylenimine (PEI). The construct was then further functionalized with siRNA and a tumor-targeting peptide, chlorotoxin (CTX), to improve tumor specificity and potency. Flow cytometry, quantitative RT-PCR, and fluorescence microscopy analyses confirmed receptor-mediated cellular internalization of nanovectors and enhanced gene knockdown through targeted siRNA delivery. The ability of this nanovector construct to generate specific contrast enhancement of glioblastoma cells was demonstrated through MR imaging. These findings suggest that this CTX enabled nanoparticle carrier may be well suited for delivery of RNAi therapeutics to brain cancer cells.

Superparamagnetic nanotraps containing MIP based mimic lipase for biotransformations uses

The nanoparticle comprises a superparamagnetic iron oxide nanoparticle core conjugated with trimethoxylsilyl propylmethacrylate (TMSPM) and methacryloylamido serine (MASE), methacryloylamido histidine (MAH), methacryloylamido glutamic acid (MAGA) monomers, and p-nitrophenyl palmitate (p-NPP) which is a substrate of lipase as a template molecule, which enables the creation of lipase active region. The resulting hybrid superparamagnetic nanotraps are magnetically separable, highly active, and stable under harsh conditions. In this study, the advantages of high selectivity of molecular imprinting technique have used to get mimic lipase for the synthesis of methyl jasmonate and methyl oleate.