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1.  Monodisperse Magnetic Nanoparticles for Theranostic Applications 
Accounts of chemical research  2011;44(10):875-882.
Conspectus
The development of highly effective medicine requires the on-time monitoring of the medical treatment process. This combination of monitoring and therapeutics allows a large degree of control on the treatment efficacy and is now commonly referred to as “theranostics”. Magnetic nanoparticles (NPs) provide a unique nano-platform for theranostic applications due to their comparable sizes with various functional biomolecules, their biocompatibility and their responses to the external magnetic field. Recent efforts in studying magnetic NPs for both imaging and therapeutic applications have led to great advances in NP fabrication with controls in dimension, surface functionalization and magnetic property. These magnetic NPs have been proven to be robust agents that can be target-specific for enhancing magnetic resonance imaging sensitivity and magnetic heating efficiency. These, plus the deep tissue penetration of magnetic field, make magnetic NPs the most promising candidates for successful theranostics in the future.
In this Account, we review the recent advances in the synthesis of magnetic NPs of iron oxide, Fe, as well as FePt and FeCo NPs for imaging and therapeutic applications. We will first introduce briefly nanomagnetism, magnetic resonance imaging (MRI), and magnetic fluid hyperthermia (MFH). We will then focus on chemical synthesis of monodisperse magnetic NPs with controlled sizes, morphologies, and magnetic properties. Typical examples in using monodisperse magnetic NPs for MRI and MFH are highlighted.
doi:10.1021/ar200090c
PMCID: PMC3184307  PMID: 21661754
2.  Biomedical Nanomagnetics: A Spin Through Possibilities in Imaging, Diagnostics, and Therapy 
IEEE transactions on magnetics  2010;46(7):2523-2558.
Biomedical nanomagnetics is a multidisciplinary area of research in science, engineering and medicine with broad applications in imaging, diagnostics and therapy. Recent developments offer exciting possibilities in personalized medicine provided a truly integrated approach, combining chemistry, materials science, physics, engineering, biology and medicine, is implemented. Emphasizing this perspective, here we address important issues for the rapid development of the field, i.e., magnetic behavior at the nanoscale with emphasis on the relaxation dynamics, synthesis and surface functionalization of nanoparticles and core-shell structures, biocompatibility and toxicity studies, biological constraints and opportunities, and in vivo and in vitro applications. Specifically, we discuss targeted drug delivery and triggered release, novel contrast agents for magnetic resonance imaging, cancer therapy using magnetic fluid hyperthermia, in vitro diagnostics and the emerging magnetic particle imaging technique, that is quantitative and sensitive enough to compete with established imaging methods. In addition, the physics of self-assembly, which is fundamental to both biology and the future development of nanoscience, is illustrated with magnetic nanoparticles. It is shown that various competing energies associated with self-assembly converge on the nanometer length scale and different assemblies can be tailored by varying particle size and size distribution. Throughout this paper, while we discuss our recent research in the broad context of the multidisciplinary literature, we hope to bridge the gap between related work in physics/chemistry/engineering and biology/medicine and, at the same time, present the essential concepts in the individual disciplines. This approach is essential as biomedical nanomagnetics moves into the next phase of innovative translational research with emphasis on development of quantitative in vivo imaging, targeted and triggered drug release, and image guided therapy including validation of delivery and therapy response.
doi:10.1109/TMAG.2010.2046907
PMCID: PMC2949969  PMID: 20930943
Biomedical engineering; diagnostics; imaging; magnetic relaxation; nanotechnology; small particles; superparamagnetism; therapy
3.  In vivo Pulsed Magneto-motive Ultrasound Imaging Using High-performance Magnetoactive Contrast Nanoagents 
Nanoscale  2013;5(22):11179-11186.
Previously, pulsed magneto-motive ultrasound (pMMUS) imaging has been introduced as a contrast-agent-assisted ultrasound-based imaging modality capable of visualizing biological events at the cellular and molecular level. In pMMUS imaging, a high intensity pulsed magnetic field is used to excite cells or tissue labeled with magnetic nanoparticles. Then, ultrasound (US) imaging is used to monitor the mechanical response of the tissue to an externally applied magnetic field (i.e., tissue displacement). Signal to noise ratio (SNR) in pMMUS imaging can be improved by using superparamagnetic nanoparticles with larger saturation magnetization. Metal-doped magnetic nanoparticles with enhanced tunable nanomagnetism are suitable candidates to improve the SNR and, therefore, sensitivity of pMMUS imaging, which is essential for in vivo pMMUS imaging. In this study, we demonstrate the capability of pMMUS imaging to identify the presence and distribution of zinc-doped iron oxide nanoparticles in live nude mice bearing A431 (human epithelial carcinoma) xenograft tumors.
doi:10.1039/c3nr03669c
PMCID: PMC3916332  PMID: 24080913
4.  Synthesis of Amine-stabilized Aqueous Colloidal Iron Oxide Nanoparticles 
Crystal growth & design  2007;7(3):471-475.
We demonstrate a simple one-step process for the synthesis of iron oxide nanoparticle aqueous colloids using the multifunctional molecule, dodecylamine (DDA), that electrostatically complexes with aqueous iron ions (one precursor Fe2+ from FeCl2), reduces them, and subsequently caps the nanoparticles. The iron oxide particles thus synthesized are of the face-centered cubic (FCC) phase with high degree of monodispersity with appropriate concentration of amine capping molecular layer. The aqueous magnetic nanocrystalline colloids were characterized by TEM, XRD, XPS, TGA/DTA and FTIR spectroscopy techniques. The relaxivity, stability, and hydrodynamic size of the nanoparticles were investigated for potential application in magnetic resonance imaging (MRI). The magnetic properties were also studied by using a superconducting quantum interference device (SQUID) magnetometer at room temperature. We believe that such simple one-step synthesis of biocompatible aqueous nanomagnetic colloids will have viable applications in biomedical imaging, diagnostics and therapeutics.
doi:10.1021/cg060656p
PMCID: PMC2659353  PMID: 19305647
5.  New Strategies to Prolong the In Vivo Life Span of Iron-Based Contrast Agents for MRI 
PLoS ONE  2013;8(10):e78542.
Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanoparticles have been developed as magnetic resonance imaging (MRI) contrast agents. Iron oxide nanoparticles, that become superparamagnetic if the core particle diameter is ~ 30nm or less, present R1 and R2 relaxivities which are much higher than those of conventional paramagnetic gadolinium chelates. Generally, these magnetic particles are coated with biocompatible polymers that prevent the agglomeration of the colloidal suspension and improve their blood distribution profile. In spite of their potential as MRI blood contrast agents, the biomedical application of iron oxide nanoparticles is still limited because of their intravascular half-life of only few hours; such nanoparticles are rapidly cleared from the bloodstream by macrophages of the reticulo-endothelial system (RES). To increase the life span of these MRI contrast agents in the bloodstream we proposed the encapsulation of SPIO nanoparticles in red blood cells (RBCs) through the transient opening of cell membrane pores. We have recently reported results obtained by applying our loading procedure to several SPIO nanoparticles with different chemical physical characteristics such as size and coating agent. In the current investigation we showed that the life span of iron-based contrast agents in the mice bloodstream was prolonged to 12 days after the intravenous injection of murine SPIO-loaded RBCs. Furthermore, we developed an animal model that implicates the pretreatment of animals with clodronate to induce a transient suppression of tissue macrophages, followed by the injection of human SPIO-loaded RBCs which make it possible to encapsulate nanoparticle concentrations (5.3-16.7mM Fe) higher than murine SPIO-loaded RBCs (1.4-3.55mM Fe). The data showed that, when human RBCs are used as more capable SPIO nanoparticle containers combined with a depletion of tissue macrophages, Fe concentration in animal blood is 2-3 times higher than iron concentration obtained by the use of murine SPIO-loaded RBCs.
doi:10.1371/journal.pone.0078542
PMCID: PMC3819506  PMID: 24223101
6.  Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress 
Iron oxide nanoparticles with unique magnetic properties have a high potential for use in several biomedical, bioengineering and in vivo applications, including tissue repair, magnetic resonance imaging, immunoassay, drug delivery, detoxification of biologic fluids, cell sorting, and hyperthermia. Although various surface modifications are being done for making these nonbiodegradable nanoparticles more biocompatible, their toxic potential is still a major concern. The current in vitro study of the interaction of superparamagnetic iron oxide nanoparticles of mean diameter 30 nm coated with Tween 80 and murine macrophage (J774) cells was undertaken to evaluate the dose- and time-dependent toxic potential, as well as investigate the role of oxidative stress in the toxicity. A 15–30 nm size range of spherical nanoparticles were characterized by transmission electron microscopy and zeta sizer. MTT assay showed >95% viability of cells in lower concentrations (25–200 μg/mL) and up to three hours of exposure, whereas at higher concentrations (300–500 μg/mL) and prolonged (six hours) exposure viability reduced to 55%–65%. Necrosis-apoptosis assay by propidium iodide and Hoechst-33342 staining revealed loss of the majority of the cells by apoptosis. H2DCFDDA assay to quantify generation of intracellular reactive oxygen species (ROS) indicated that exposure to a higher concentration of nanoparticles resulted in enhanced ROS generation, leading to cell injury and death. The cell membrane injury induced by nanoparticles studied using the lactate dehydrogenase assay, showed both concentration- and time-dependent damage. Thus, this study concluded that use of a low optimum concentration of superparamagnetic iron oxide nanoparticles is important for avoidance of oxidative stress-induced cell injury and death.
doi:10.2147/IJN.S13244
PMCID: PMC3010160  PMID: 21187917
superparamagnetic iron oxide nanoparticles; cytotoxicity; MTT assay; J774 cell line
7.  Safety Implications of High-Field MRI: Actuation of Endogenous Magnetic Iron Oxides in the Human Body 
PLoS ONE  2009;4(5):e5431.
Background
Magnetic Resonance Imaging scanners have become ubiquitous in hospitals and high-field systems (greater than 3 Tesla) are becoming increasingly common. In light of recent European Union moves to limit high-field exposure for those working with MRI scanners, we have evaluated the potential for detrimental cellular effects via nanomagnetic actuation of endogenous iron oxides in the body.
Methodology
Theoretical models and experimental data on the composition and magnetic properties of endogenous iron oxides in human tissue were used to analyze the forces on iron oxide particles.
Principal Finding and Conclusions
Results show that, even at 9.4 Tesla, forces on these particles are unlikely to disrupt normal cellular function via nanomagnetic actuation.
doi:10.1371/journal.pone.0005431
PMCID: PMC2673027  PMID: 19412550
8.  Magnetomotive Molecular Nanoprobes 
Current Medicinal Chemistry  2011;18(14):2103-2114.
Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogen-induced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications.
PMCID: PMC3319747  PMID: 21517766
Magnetomotion; molecular imaging; optical coherence tomography; hyperthermia; superparamagnetic iron oxide nanoparticles; targeting
9.  Gum arabic modified Fe3O4 nanoparticles cross linked with collagen for isolation of bacteria 
Background
Multifunctional magnetic nanoparticles are important class of materials in the field of nanobiotechnology, as it is an emerging area of research for material science and molecular biology researchers. One of the various methods to obtain multifunctional nanomaterials, molecular functionalization by attaching organic functional groups to nanomagnetic materials is an important technique. Recently, functionalized magnetic nanoparticles have been demonstrated to be useful in isolation/detection of dangerous pathogens (bacteria/viruses) for human life. Iron (Fe) based material especially FePt is used in the isolation of ultralow concentrations (< 102 cfu/ml) of bacteria in less time and it has been demonstrated that van-FePt may be used as an alternative fast detection technique with respect to conventional polymerase chain reaction (PCR) method. However, still further improved demonstrations are necessary with interest to biocompatibility and green chemistry. Herein, we report the synthesis of Fe3O4 nanoparticles by template medication and its application for the detection/isolation of S. aureus bacteria.
Results
The reduction of anhydrous Iron chloride (FeCl3) in presence of sodium borohydride and water soluble polyelectrolyte (polydiallyldimethyl ammonium chloride, PDADMAC) produces black precipitates. The X-ray diffraction (XRD), XPS and TEM analysis of the precipitates dried at 373 K demonstrated the formation of nanocrystalline Fe3O4. Moreover, scanning electron microscopy (SEM) showed isolated staphylococcous aureus (S. aureus) bacteria at ultralow concentrations using collagen coated gum arabic modified iron oxide nanoparticles (CCGAMION).
Conclusion
We are able to synthesize nanocrystalline Fe3O4 and CCGAMION was able to isolate S. aureus bacteria at 8-10 cfu (colony forming units)/ml within ~3 minutes.
doi:10.1186/1477-3155-8-30
PMCID: PMC3018424  PMID: 21159158
10.  Profiling and quantitative evaluation of three Nickel-Coated magnetic matrices for purification of recombinant proteins: lelpful hints for the optimized nanomagnetisable matrix preparation 
Background
Several materials are available in the market that work on the principle of protein magnetic fishing by their histidine (His) tags. Little information is available on their performance and it is often quoted that greatly improved purification of histidine-tagged proteins from crude extracts could be achieved. While some commercial magnetic matrices could be used successfully for purification of several His-tagged proteins, there are some which have been proved to operate just for a few extent of His-tagged proteins. Here, we address quantitative evaluation of three commercially available Nickel nanomagnetic beads for purification of two His-tagged proteins expressed in Escherichia coli and present helpful hints for optimized purification of such proteins and preparation of nanomagnetisable matrices.
Results
Marked differences in the performance of nanomagnetic matrices, principally on the basis of their specific binding capacity, recovery profile, the amount of imidazole needed for protein elution and the extent of target protein loss and purity were obtained. Based on the aforesaid criteria, one of these materials featured the best purification results (SiMAG/N-NTA/Nickel) for both proteins at the concentration of 4 mg/ml, while the other two (SiMAC-Nickel and SiMAG/CS-NTA/Nickel) did not work well with respect to specific binding capacity and recovery profile.
Conclusions
Taken together, functionality of different types of nanomagnetic matrices vary considerably. This variability may not only be dependent upon the structure and surface chemistry of the matrix which in turn determine the affinity of interaction, but, is also influenced to a lesser extent by the physical properties of the protein itself. Although the results of the present study may not be fully applied for all nanomagnetic matrices, but provide a framework which could be used to profiling and quantitative evaluation of other magnetisable matrices and also provide helpful hints for those researchers facing same challenge.
doi:10.1186/1477-3155-9-31
PMCID: PMC3163181  PMID: 21824404
11.  Conquering the Dark Side: Colloidal Iron Oxide Nanoparticles 
ACS nano  2009;3(12):3917-3926.
Nanomedicine approaches to atherosclerotic disease will have significant impact on the practice and outcomes of cardiovascular medicine. Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects that can only be imaged 24 or more hours after systemic administration due to persistent blood pool interference. Although recent advances involving MR pulse sequences have converted these dark contrast voxels into bright ones, the marked delays in imaging from persistent magnetic background interference and prominent dipole blooming effects of the magnetic susceptibility remain barriers to overcome. We report a T1-weighted (T1w) theranostic colloidal iron oxide nanoparticle platform, CION, which is achieved by entrapping oleate-coated magnetite particles within a cross-linked phospholipid nanoemulsion. Contrary to expectations, this formulation decreased T2 effects thus allowing positive T1w contrast detection down to low nanomolar concentrations. CION, a vascular constrained nanoplatform administered in vivo permitted T1w molecular imaging 1 hour after treatment without blood pool interference, although some T2 shortening effects on blood, induced by the superparamagnetic particles persisted. Moreover, CION was shown to encapsulate antiangiogenic drugs, like fumagillin, and retained them under prolonged dissolution, suggesting significant theranostic functionality. Overall, CION is a platform technology, developed with generally recognized as safe components, that overcomes the temporal and spatial imaging challenges associated with current iron oxide nanoparticle T2 imaging agents, and which has theranostic potential in vascular diseases for detecting unstable ruptured plaque or treating atherosclerotic angiogenesis.
doi:10.1021/nn900819y
PMCID: PMC2797561  PMID: 19908850
iron oxide; molecular imaging; drug delivery; angiogenesis; ruptured plaque; MRI
12.  Multifunctional Magnetic-fluorescent Nanocomposites for Biomedical Applications 
Nanoscale Research Letters  2008;3(3):87-104.
Nanotechnology is a fast-growing area, involving the fabrication and use of nano-sized materials and devices. Various nanocomposite materials play a number of important roles in modern science and technology. Magnetic and fluorescent inorganic nanoparticles are of particular importance due to their broad range of potential applications. It is expected that the combination of magnetic and fluorescent properties in one nanocomposite would enable the engineering of unique multifunctional nanoscale devices, which could be manipulated using external magnetic fields. The aim of this review is to present an overview of bimodal “two-in-one” magnetic-fluorescent nanocomposite materials which combine both magnetic and fluorescent properties in one entity, in particular those with potential applications in biotechnology and nanomedicine. There is a great necessity for the development of these multifunctional nanocomposites, but there are some difficulties and challenges to overcome in their fabrication such as quenching of the fluorescent entity by the magnetic core. Fluorescent-magnetic nanocomposites include a variety of materials including silica-based, dye-functionalised magnetic nanoparticles and quantum dots-magnetic nanoparticle composites. The classification and main synthesis strategies, along with approaches for the fabrication of fluorescent-magnetic nanocomposites, are considered. The current and potential biomedical uses, including biological imaging, cell tracking, magnetic bioseparation, nanomedicine and bio- and chemo-sensoring, of magnetic-fluorescent nanocomposites are also discussed.
doi:10.1007/s11671-008-9122-8
PMCID: PMC3244791
Nanoparticles; Magnetic particles; Fluorescence; Quantum dots; Biological imaging; Cells; Nanomedicine
13.  Casein-coated Iron Oxide Nanoparticles for High MRI Contrast Enhancement and Efficient Cell Targeting 
ACS applied materials & interfaces  2013;5(11):4632-4639.
Surface properties, as well as inherent physicochemical properties, of the engineered nanomaterials play important roles in their interactions with the biological systems, which eventually affect their efficiency in diagnostic and therapeutic applications. Here we report a new class MRI contrast agent based on milk casein protein coated iron oxide nanoparticles (CNIOs) with a core size of 15 nm and hydrodynamic diameter ~30 nm. These CNIOs exhibited excellent water-solubility, colloidal stability, and biocompatibility. Importantly, CNIOs exhibited prominent T2 enhancing capability with a transverse relaxivity r2 of 273 mM−1s−1 at 3 Tesla. The transverse relaxivity is ~2.5-fold higher than that of iron oxide nanoparticles with the same core but an amphiphilic polymer coating. CNIOs showed pH-responsive properties, formed loose and soluble aggregates near the pI (pH~4.0). The aggregates could be dissociated reversibly when the solution pH was adjusted away from the pI. The transverse relaxation property and MRI contrast enhancing effect of CNIOs remained unchanged in the pH range of 2.0 to 8.0. Further functionalization of CNIOs can be achieved via surface modification of the protein coating. Bio-affinitive ligands, such as a single chain fragment from the antibody of epidermal growth factor receptor (ScFvEGFR), could be readily conjugated onto the protein coating, enabling specific targeting to MDA-MB-231 breast cancer cells over-expressing EGFR. T2-weighted MRI of mice intravenously administered with CNIOs demonstrated strong contrast enhancement in the liver and spleen. These favorable properties suggest CNIOs as a class of biomarker targeted magnetic nanoparticles for MRI contrast enhancement and related biomedical applications.
doi:10.1021/am400713j
PMCID: PMC3699787  PMID: 23633522
iron; oxide; nanoparticles; magnetic resonance; imaging; casein; contrast agent; targeting
14.  Hard magnetic ferrite with a gigantic coercivity and high frequency millimetre wave rotation 
Nature Communications  2012;3:1035-.
Magnetic ferrites such as Fe3O4 and Fe2O3 are extensively used in a range of applications because they are inexpensive and chemically stable. Here we show that rhodium-substituted ε-Fe2O3, ε-RhxFe2−xO3 nanomagnets prepared by a nanoscale chemical synthesis using mesoporous silica as a template, exhibit a huge coercive field (Hc) of 27 kOe at room temperature. Furthermore, a crystallographically oriented sample recorded an Hc value of 31 kOe, which is the largest value among metal-oxide-based magnets and is comparable to those of rare-earth magnets. In addition, ε-RhxFe2−xO3 shows high frequency millimetre wave absorption up to 209 GHz. ε-Rh0.14Fe1.86O3 exhibits a rotation of the polarization plane of the propagated millimetre wave at 220 GHz, which is one of the promising carrier frequencies (the window of air) for millimetre wave wireless communications.
Permanent magnets based on magnetic ferrites such as Fe3O4 and Fe2O3 are used in a wide range of applications. This study demonstrates that introducing rhodium into nanoparticles consisting of the ε phase of Fe2O3 gives rise to a very high coercivity.
doi:10.1038/ncomms2038
PMCID: PMC3658006  PMID: 22948817
15.  Recent Advances in Superparamagnetic Iron Oxide Nanoparticles for Cellular Imaging and Targeted Therapy Research 
Current Pharmaceutical Design  2013;19(37):6575-6593.
Advances of nanotechnology have led to the development of nanomaterials with both potential diagnostic and therapeutic applications. Among them, superparamagnetic iron oxide (SPIO) nanoparticles have received particular attention. Over the past decade, various SPIOs with unique physicochemical and biological properties have been designed by modifying the particle structure, size and coating. This article reviews the recent advances in preparing SPIOs with novel properties, the way these physicochemical properties of SPIOs influence their interaction with cells, and the development of SPIOs in liver and lymph nodes magnetic resonance imaging (MRI) contrast. Cellular uptake of SPIO can be exploited in a variety of potential clinical applications, including stem cell and inflammation cell tracking and intra-cellular drug delivery to cancerous cells which offers higher intra-cellular concentration. When SPIOs are used as carrier vehicle, additional advantages can be achieved including magnetic targeting and hyperthermia options, as well as monitoring with MRI. Other potential applications of SPIO include magnetofection and gene delivery, targeted retention of labeled stem cells, sentinel lymph nodes mapping, and magnetic force targeting and cell orientation for tissue engineering.
doi:10.2174/1381612811319370003
PMCID: PMC4082310  PMID: 23621536
Superparamagnetic; iron oxide nanoparticles; SPIO; cell labeling; surface coatings; MRI; targeted drug delivery; magnetic targeting; hyperthermia.
16.  Improving the Magnetic Resonance Imaging Contrast and Detection Methods with Engineered Magnetic Nanoparticles 
Theranostics  2012;2(1):86-102.
Engineering and functionalizing magnetic nanoparticles have been an area of the extensive research and development in the biomedical and nanomedicine fields. Because their biocompatibility and toxicity are well investigated and better understood, magnetic nanoparticles, especially iron oxide nanoparticles, are better suited materials as contrast agents for magnetic resonance imaging (MRI) and for image-directed delivery of therapeutics. Given tunable magnetic properties and various surface chemistries from the coating materials, most applications of engineered magnetic nanoparticles take advantages of their superb MRI contrast enhancing capability as well as surface functionalities. It has been found that MRI contrast enhancement by magnetic nanoparticles is highly dependent on the composition, size and surface properties as well as the degree of aggregation of the nanoparticles. Therefore, understanding the relationships between these intrinsic parameters and the relaxivities that contribute to MRI contrast can lead to establishing essential guidance that may direct the design of engineered magnetic nanoparticles for theranostics applications. On the other hand, new contrast mechanism and imaging strategy can be developed based on the novel properties of engineered magnetic nanoparticles. This review will focus on discussing the recent findings on some chemical and physical properties of engineered magnetic nanoparticles affecting the relaxivities as well as the impact on MRI contrast. Furthermore, MRI methods for imaging magnetic nanoparticles including several newly developed MRI approaches aiming at improving the detection and quantification of the engineered magnetic nanoparticles are described.
doi:10.7150/thno.4006
PMCID: PMC3263519  PMID: 22272222
magnetic nanoparticles; engineering; functionalizing; magnetic resonance imaging
17.  Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content 
Purpose
Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations.
Materials and methods
Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity.
Results
No cytotoxicity was observed at twice the target intracellular iron concentration (~100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties.
Conclusions
This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.
doi:10.3109/02656736.2014.913321
PMCID: PMC4327906  PMID: 24773041
Magnetic iron oxide nanoparticles; magnetic nanoparticle hyperthermia; magnetic resonance imaging; cancer
18.  Free-Standing Magnetic Nanopillars for 3D Nanomagnet Logic 
ACS Applied Materials & Interfaces  2014;6(22):20254-20260.
Nanomagnet logic (NML) is a relatively new computation technology that uses arrays of shape-controlled nanomagnets to enable digital processing. Currently, conventional resist-based lithographic processes limit the design of NML circuitry to planar nanostructures with homogeneous thicknesses. Here, we demonstrate the focused electron beam induced deposition of Fe-based nanomaterial for magnetic in-plane nanowires and out-of-plane nanopillars. Three-dimensional (3D) NML was achieved based on the magnetic coupling between nanowires and nanopillars in a 3D array. Additionally, the same Fe-based nanomaterial was used to produce tilt-corrected high-aspect-ratio probes for the accurate magnetic force microscopy (MFM) analysis of the fabricated 3D NML gate arrays. The interpretation of the MFM measurements was supported by magnetic simulations using the Object Oriented MicroMagnetic Framework. Introducing vertical out-of-plane nanopillars not only increases the packing density of 3D NML but also introduces an extra magnetic degree of freedom, offering a new approach to input/output and processing functionalities in nanomagnetic computing.
doi:10.1021/am505785t
PMCID: PMC4251043  PMID: 25296008
nanomagnet logic; electron beam induced deposition; iron; magnetic nanowires; nanomagnetism; MFM; computational nanotechnology
19.  Powerful inner/outer controlled multi-target magnetic nanoparticle drug carrier prepared by liquid photo-immobilization 
Scientific Reports  2014;4:4990.
Nanomagnetic materials offer exciting avenues for advancing cancer therapies. Most researches have focused on efficient delivery of drugs in the body by incorporating various drug molecules onto the surface of nanomagnetic particles. The challenge is how to synthesize low toxic nanocarriers with multi-target drug loading. The cancer cell death mechanisms associated with those nanocarriers remain unclear either. Following the cell biology mechanisms, we develop a liquid photo-immobilization approach to attach doxorubicin, folic acid, tumor necrosis factor-α, and interferon-γ onto the oleic acid molecules coated Fe3O4 magnetic nanoparticles to prepare a kind of novel inner/outer controlled multi-target magnetic nanoparticle drug carrier. In this work, this approach is demonstrated by a variety of structural and biomedical characterizations, addressing the anti-cancer effects in vivo and in vitro on the HeLa, and it is highly efficient and powerful in treating cancer cells in a valuable programmed cell death mechanism for overcoming drug resistance.
doi:10.1038/srep04990
PMCID: PMC4028896  PMID: 24845203
20.  Removal of crystal violet from water by magnetically modified activated carbon and nanomagnetic iron oxide 
Magnetically modified activated carbon, which synthesized by nanomagnetic iron oxide, was used for fast and effective removal of Crystal Violet from aqueous solutions. The scanning electron microscopy (SEM) images of nano-adsorbent showed that the average sizes of adsorbent are less than 100 nm. The various parameters, affecting on adsorption process, were examined including pH and temperature of dye solution, dose of adsorbent, and contact time. Then, thermodynamic parameters of sorption were calculated. Langmuir and Freundlich isotherms were used to fit the resulting data. Adsorption kinetics was consistent with a pseudo second order equation. Thermodynamic parameters of adsorption, ∆H0, and ∆S0 were calculated. Also, for further investigations, nano magnetic iron oxides was synthesized and used as adsorbent. Sorption capacities were depending on the temperature varied from 44.7 to 67.1 mg/g and from 12.7 to 16.5 mg/g for magnetically modified activated carbon and nanomagnetic iron oxide, respectively.
doi:10.1186/s40201-015-0156-4
PMCID: PMC4333261
Magnetically modified activated carbon; Crystal Violet; Langmuir isotherm; Freundlich isotherm; Nano magnetic iron oxide
21.  Biofunctionalized magnetic-vortex microdiscs for targeted cancer-cell destruction 
Nature materials  2009;9(2):165-171.
Nanomagnetic materials offer exciting avenues for probing cell mechanics and activating mechanosensitive ion channels, as well as for advancing cancer therapies. Most experimental works so far have used superparamagnetic materials. This report describes a first approach based on interfacing cells with lithographically defined microdiscs that possess a spin-vortex ground state. When an alternating magnetic field is applied the microdisc vortices shift, creating an oscillation, which transmits a mechanical force to the cell. Because reduced sensitivity of cancer cells toward apoptosis leads to inappropriate cell survival and malignant progression, selective induction of apoptosis is of great importance for the anticancer therapeutic strategies. We show that the spin-vortex-mediated stimulus creates two dramatic effects: compromised integrity of the cellular membrane, and initiation of programmed cell death. A low-frequency field of a few tens of hertz applied for only ten minutes was sufficient to achieve ~90% cancer-cell destruction in vitro.
doi:10.1038/nmat2591
PMCID: PMC2810356  PMID: 19946279
22.  Preparation and in vitro evaluation of doxorubicin-loaded Fe3O4 magnetic nanoparticles modified with biocompatible copolymers 
Background
Superparamagnetic iron oxide nanoparticles are attractive materials that have been widely used in medicine for drug delivery, diagnostic imaging, and therapeutic applications. In our study, superparamagnetic iron oxide nanoparticles and the anticancer drug, doxorubicin hydrochloride, were encapsulated into poly (D, L-lactic-co-glycolic acid) poly (ethylene glycol) (PLGA-PEG) nanoparticles for local treatment. The magnetic properties conferred by superparamagnetic iron oxide nanoparticles could help to maintain the nanoparticles in the joint with an external magnet.
Methods
A series of PLGA:PEG triblock copolymers were synthesized by ring-opening polymerization of D, L-lactide and glycolide with different molecular weights of polyethylene glycol (PEG2000, PEG3000, and PEG4000) as an initiator. The bulk properties of these copolymers were characterized using 1H nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared spectroscopy, and differential scanning calorimetry. In addition, the resulting particles were characterized by x-ray powder diffraction, scanning electron microscopy, and vibrating sample magnetometry.
Results
The doxorubicin encapsulation amount was reduced for PLGA:PEG2000 and PLGA:PEG3000 triblock copolymers, but increased to a great extent for PLGA:PEG4000 triblock copolymer. This is due to the increased water uptake capacity of the blended triblock copolymer, which encapsulated more doxorubicin molecules into a swollen copolymer matrix. The drug encapsulation efficiency achieved for Fe3O4 magnetic nanoparticles modified with PLGA:PEG2000, PLGA:PEG3000, and PLGA:PEG4000 copolymers was 69.5%, 73%, and 78%, respectively, and the release kinetics were controlled. The in vitro cytotoxicity test showed that the Fe3O4-PLGA:PEG4000 magnetic nanoparticles had no cytotoxicity and were biocompatible.
Conclusion
There is potential for use of these nanoparticles for biomedical application. Future work includes in vivo investigation of the targeting capability and effectiveness of these nanoparticles in the treatment of lung cancer.
doi:10.2147/IJN.S24326
PMCID: PMC3273983  PMID: 22334781
superparamagnetic iron oxide nanoparticles; triblock copolymer; doxorubicin encapsulation; water uptake; drug encapsulation efficiency
23.  Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers 
A targeted drug delivery system is the need of the hour. Guiding magnetic iron oxide nanoparticles with the help of an external magnetic field to its target is the principle behind the development of superparamagnetic iron oxide nanoparticles (SPIONs) as novel drug delivery vehicles. SPIONs are small synthetic γ-Fe2O3 (maghemite) or Fe3O4 (magnetite) particles with a core ranging between 10 nm and 100 nm in diameter. These magnetic particles are coated with certain biocompatible polymers, such as dextran or polyethylene glycol, which provide chemical handles for the conjugation of therapeutic agents and also improve their blood distribution profile. The current research on SPIONs is opening up wide horizons for their use as diagnostic agents in magnetic resonance imaging as well as for drug delivery vehicles. Delivery of anticancer drugs by coupling with functionalized SPIONs to their targeted site is one of the most pursued areas of research in the development of cancer treatment strategies. SPIONs have also demonstrated their efficiency as nonviral gene vectors that facilitate the introduction of plasmids into the nucleus at rates multifold those of routinely available standard technologies. SPION-induced hyperthermia has also been utilized for localized killing of cancerous cells. Despite their potential biomedical application, alteration in gene expression profiles, disturbance in iron homeostasis, oxidative stress, and altered cellular responses are some SPION-related toxicological aspects which require due consideration. This review provides a comprehensive understanding of SPIONs with regard to their method of preparation, their utility as drug delivery vehicles, and some concerns which need to be resolved before they can be moved from bench top to bedside.
doi:10.2147/IJN.S30320
PMCID: PMC3405876  PMID: 22848170
superparamagnetic iron oxide nanoparticles; SPIONs; targeted delivery; coating; functionalization; targeting ligands; toxicity
24.  Effects of Mesoporous Silica Coating and Post-Synthetic Treatment on the Transverse Relaxivity of Iron Oxide Nanoparticles 
Mesoporous silica nanoparticles have the capacity to load and deliver therapeutic cargo and incorporate imaging modalities, making them prominent candidates for theranostic devices. One of the most widespread imaging agents utilized in this and other theranostic platforms is nanoscale superparamagnetic iron oxide. Although several core-shell magnetic mesoporous silica nanoparticles presented in the literature have provided high T2 contrast in vitro and in vivo, there is ambiguity surrounding which parameters lead to enhanced contrast. Additionally, there is a need to understand the behavior of these imaging agents over time in biologically relevant environments. Herein, we present a systematic analysis of how the transverse relaxivity (r2) of magnetic mesoporous silica nanoparticles is influenced by nanoparticle diameter, iron oxide nanoparticle core synthesis, and the use of a hydrothermal treatment. This work demonstrates that samples which did not undergo a hydrothermal treatment experienced a drop in r2 (75% of original r2 within 8 days of water storage), while samples with hydrothermal treatment maintained roughly the same r2 for over 30 days in water. Our results suggest that iron oxide oxidation is the cause of the r2 loss, and this oxidation can be prevented both during synthesis and storage by the use of deoxygenated conditions during nanoparticle synthesis. The hydrothermal treatment also provides colloidal stability, even in acidic and highly salted solutions, and a resistance against acid degradation of the iron oxide nanoparticle core. The results of this study show the promise of multifunctional mesoporous silica nanoparticles but will also likely inspire further investigation into multiples types of theranostic devices, taking into consideration their behavior over time and in relevant biological environments.
doi:10.1021/cm400711h
PMCID: PMC3694606  PMID: 23814377
transverse relaxivity; mesoporous silica; iron oxide; nanoparticles; hydrothermal treatment
25.  Induction of Biogenic Magnetization and Redox Control by a Component of the Target of Rapamycin Complex 1 Signaling Pathway 
PLoS Biology  2012;10(2):e1001269.
Most organisms are simply diamagnetic, while magnetotactic bacteria and migratory animals are among organisms that exploit magnetism. Biogenic magnetization not only is of fundamental interest, but also has industrial potential. However, the key factor(s) that enable biogenic magnetization in coordination with other cellular functions and metabolism remain unknown. To address the requirements for induction and the application of synthetic bio-magnetism, we explored the creation of magnetism in a simple model organism. Cell magnetization was first observed by attraction towards a magnet when normally diamagnetic yeast Saccharomyces cerevisiae were grown with ferric citrate. The magnetization was further enhanced by genetic modification of iron homeostasis and introduction of ferritin. The acquired magnetizable properties enabled the cells to be attracted to a magnet, and be trapped by a magnetic column. Superconducting quantum interference device (SQUID) magnetometry confirmed and quantitatively characterized the acquired paramagnetism. Electron microscopy and energy-dispersive X-ray spectroscopy showed electron-dense iron-containing aggregates within the magnetized cells. Magnetization-based screening of gene knockouts identified Tco89p, a component of TORC1 (Target of rapamycin complex 1), as important for magnetization; loss of TCO89 and treatment with rapamycin reduced magnetization in a TCO89-dependent manner. The TCO89 expression level positively correlated with magnetization, enabling inducible magnetization. Several carbon metabolism genes were also shown to affect magnetization. Redox mediators indicated that TCO89 alters the intracellular redox to an oxidized state in a dose-dependent manner. Taken together, we demonstrated that synthetic induction of magnetization is possible and that the key factors are local redox control through carbon metabolism and iron supply.
Author Summary
Most organisms do not respond to magnetic fields. However, “magnetotactic” bacteria and migratory animals can sense geomagnetic fields and alter their behavior accordingly. These organisms often contain small magnetic particles that may be responsible for sensing magnetic fields. In magnetotactic bacteria, specific genes are crucial for the formation of these magnetic particles, but no such genes have yet been characterized in migratory animals. In humans, formation of magnetic particles can be observed in the neuronal tissue in neurodegenerative diseases. One explanation for the appearance of these magnetic particles is that they are the result of alterations in metabolism, which occur in neurodegenerative diseases. Here, we explore this hypothesis by inducing magnetism in yeast cells, which are not naturally magnetic and examine how changes in metabolism contribute to particle formation and magnetism. We find that yeast cells expressing a set of human proteins that sequester iron contain iron particles and become attracted by a magnet when grown with ferric citrate. Through physiological and genetic studies we show that target of rapamycin complex 1 (TORC1) signaling, which responds to nutritional signals, is important for the magnetization of these cells by altering the intracellular oxidation (or redox) state. We also show that genes involved in carbon metabolism affect magnetization. We propose that local redox control mediated by carbon metabolism and iron homeostasis, processes that exist in normal unmagnetized cells, are key for iron particle formation and magnetization. We conclude that magnetization of normal cells will be possible with these existing gene sets.
doi:10.1371/journal.pbio.1001269
PMCID: PMC3289596  PMID: 22389629

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