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1.  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.
PMCID: PMC2949969  PMID: 20930943
Biomedical engineering; diagnostics; imaging; magnetic relaxation; nanotechnology; small particles; superparamagnetism; therapy
2.  Safety Implications of High-Field MRI: Actuation of Endogenous Magnetic Iron Oxides in the Human Body 
PLoS ONE  2009;4(5):e5431.
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.
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.
PMCID: PMC2673027  PMID: 19412550
3.  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.
PMCID: PMC3010160  PMID: 21187917
superparamagnetic iron oxide nanoparticles; cytotoxicity; MTT assay; J774 cell line
4.  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.
PMCID: PMC3819506  PMID: 24223101
5.  Materials Characterization of Feraheme/Ferumoxytol and Preliminary Evaluation of Its Potential for Magnetic Fluid Hyperthermia 
Feraheme, is a recently FDA-cleared superparamagnetic iron oxide nanoparticle (SPION)-based MRI contrast agent that is also employed in the treatment of iron deficiency anemia. Feraheme nanoparticles have a hydrodynamic diameter of 30 nm and consist of iron oxide crystallites complexed with a low molecular weight, semi-synthetic carbohydrate. These features are attractive for other potential biomedical applications such as magnetic fluid hyperthermia (MFH), since the carboxylated polymer coating affords functionalization of the particle surface and the size allows for accumulation in highly vascularized tumors via the enhanced permeability and retention effect. This work presents morphological and magnetic characterization of Feraheme by transmission electron microscopy (TEM), Energy dispersive X-ray spectroscopy (EDX), and superconducting quantum interference device (SQUID) magnetometry. Additionally, the results of an initial evaluation of the suitability of Feraheme for MFH applications are described, and the data indicate the particles possess promising properties for this application.
PMCID: PMC3794737  PMID: 24065092
Feraheme; magnetic fluid hyperthermia; magnetic nanoparticles; MRI contrast
6.  Distinguishing magnetic and electrostatic interactions by a Kelvin probe force microscopy–magnetic force microscopy combination 
The most outstanding feature of scanning force microscopy (SFM) is its capability to detect various different short and long range interactions. In particular, magnetic force microscopy (MFM) is used to characterize the domain configuration in ferromagnetic materials such as thin films grown by physical techniques or ferromagnetic nanostructures. It is a usual procedure to separate the topography and the magnetic signal by scanning at a lift distance of 25–50 nm such that the long range tip–sample interactions dominate. Nowadays, MFM is becoming a valuable technique to detect weak magnetic fields arising from low dimensional complex systems such as organic nanomagnets, superparamagnetic nanoparticles, carbon-based materials, etc. In all these cases, the magnetic nanocomponents and the substrate supporting them present quite different electronic behavior, i.e., they exhibit large surface potential differences causing heterogeneous electrostatic interaction between the tip and the sample that could be interpreted as a magnetic interaction. To distinguish clearly the origin of the tip–sample forces we propose to use a combination of Kelvin probe force microscopy (KPFM) and MFM. The KPFM technique allows us to compensate in real time the electrostatic forces between the tip and the sample by minimizing the electrostatic contribution to the frequency shift signal. This is a great challenge in samples with low magnetic moment. In this work we studied an array of Co nanostructures that exhibit high electrostatic interaction with the MFM tip. Thanks to the use of the KPFM/MFM system we were able to separate the electric and magnetic interactions between the tip and the sample.
PMCID: PMC3190625  PMID: 22003461
electrostatic interaction; focused electron beam induced deposition; Kelvin probe force microscopy; magnetic force microscopy; magnetic nanostructures
7.  Preparation and in vitro evaluation of doxorubicin-loaded Fe3O4 magnetic nanoparticles modified with biocompatible copolymers 
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.
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.
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.
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.
PMCID: PMC3273983  PMID: 22334781
superparamagnetic iron oxide nanoparticles; triblock copolymer; doxorubicin encapsulation; water uptake; drug encapsulation efficiency
8.  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.
PMCID: PMC3658006  PMID: 22948817
9.  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.
PMCID: PMC2797561  PMID: 19908850
iron oxide; molecular imaging; drug delivery; angiogenesis; ruptured plaque; MRI
10.  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.
PMCID: PMC3263519  PMID: 22272222
magnetic nanoparticles; engineering; functionalizing; magnetic resonance imaging
11.  Magnetic Nanoparticles for Cancer Diagnosis and Therapy 
Pharmaceutical research  2012;29(5):1180-1188.
Nanotechnology is evolving as a new field that has a potentially high research and clinical impact. Medicine, in particular, could benefit from nanotechnology, due to emerging applications for noninvasive imaging and therapy. One important nanotechnological platform that has shown promise includes the so-called iron oxide nanoparticles. With specific relevance to cancer therapy, iron oxide nanoparticle-based therapy represents an important alternative to conventional chemotherapy, radiation, or surgery. Iron oxide nanoparticles are usually composed of three main components: an iron core, a polymer coating, and functional moieties. The biodegradable iron core can be designed to be superparamagnetic. This is particularly important, if the nanoparticles are to be used as a contrast agent for noninvasive magnetic resonance imaging (MRI). Surrounding the iron core is generally a polymer coating, which not only serves as a protective layer but also is a very important component for transforming nanoparticles into biomedical nanotools for in vivo applications. Finally, different moieties attached to the coating serve as targeting macromolecules, therapeutics payloads, or additional imaging tags. Despite the development of several nanoparticles for biomedical applications, we believe that iron oxide nanoparticles are still the most promising platform that can transform nanotechnology into a conventional medical discipline.
PMCID: PMC3734862  PMID: 22274558
cancer; diagnosis; drug delivery; gene delivery; iron oxide nanoparticle; magnetic nanoparticle; molecular imaging; MRI; nanomedicine; siRNA; therapy
12.  Preparation and Characterization of a Magnetic and Optical Dual-Modality Molecular Probe 
Nanotechnology  2010;21(17):175704.
Multi-modality imaging probes combine the advantages of individual imaging techniques to yield highly detailed anatomic and molecular information in living organisms. Herein, we report the synthesis and characterization of a dual-modality nanoprobe that couples the magnetic properties of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with the near infrared fluorescence of Cy5.5. The fluorophore is encapsulated in a biocompatible shell of silica surrounding the iron oxide core for a final diameter of ~17 nm. This silica-coated iron oxide nanoparticle (SCION) has been analyzed by transmission electron microscopy, dynamic light scattering, and superconducting quantum interference device (SQUID). The particle demonstrates a strong negative surface charge and maintains colloidal stability in the physiological pH range. Magnetic hysteresis analysis confirms superparamagnetic properties that could be manipulated for thermotherapy. The viability of primary human monocytes, T cells, and B cells incubated with particle has been examined in vitro. In vivo analysis of agent leakage into subcutaneous A431 tumors in mice was also conducted. This particle has been designed for diagnostic application with magnetic resonance and fluorescence imaging, and has future potential to serve as a heat-sensitive targeted drug delivery platform.
PMCID: PMC2859998  PMID: 20368682
13.  Gum arabic modified Fe3O4 nanoparticles cross linked with collagen for isolation of bacteria 
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.
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).
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.
PMCID: PMC3018424  PMID: 21159158
14.  Enhanced pulsed magneto-motive ultrasound imaging using superparamagnetic nanoclusters 
Nanotechnology  2010;22(4):045502.
Recently, pulsed magneto-motive ultrasound (pMMUS) imaging augmented with ultra-small magnetic nanoparticles has been introduced as a tool capable of imaging events at molecular and cellular levels. The sensitivity of a pMMUS system depends on several parameters, including the size, geometry and magnetic properties of the nanoparticles. Under the same magnetic field, larger magnetic nanostructures experience a stronger magnetic force and produce larger displacement, thus improving the sensitivity and signal-to-noise ratio (SNR) of pMMUS imaging. Unfortunately, large magnetic iron-oxide nanoparticles are typically ferromagnetic and thus are very difficult to stabilize against colloidal aggregation. In the current study we demonstrate improvement of pMMUS image quality by using large size superparamagnetic nanoclusters characterized by strong magnetization per particle. Water-soluble magnetic nanoclusters of two sizes (15 and 55 nm average size) were synthesized from 3 nm iron precursors in the presence of citrate capping ligand. The size distribution of synthesized nanoclusters and individual nanoparticles was characterized using dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM). Tissue mimicking phantoms containing single nanoparticles and two sizes of nanoclusters were imaged using a custom-built pMMUS imaging system. While the magnetic properties of citrate-coated nanoclusters are identical to those of superparamagnetic nanoparticles, the magneto-motive signal detected from nanoclusters is larger, i.e. the same magnetic field produced larger magnetically induced displacement. Therefore, our study demonstrates that clusters of superparamagnetic nanoparticles result in pMMUS images with higher contrast and SNR.
PMCID: PMC3059156  PMID: 21157009
15.  Size-Tunable Synthesis of Stable Superparamagnetic Iron Oxide Nanoparticles for Potential Biomedical Applications 
Dextran-coated superparamagnetic nanoparticles (MNPs) have widespread biomedical applications. The superparamagnetic behavior, specifically regulated size, and smooth morphology are crucial requirements for essentially all of these applications. Presented herein is an innovative double-coating strategy that would allow for a size-controlled synthesis of MNPs. Small monocrystalline iron oxide nanoparticles (MIONs) were first synthesized, which served as the source of superparamagnetic properties. These MIONs were then treated in an acetate buffer containing biocompatible dextran polymer. Under such an environment, the colloidal MIONs would be quickly agglomerated by the acetate ions, and the formed coalescent body of MION would then be stabilized simultaneously by coating with dextran. By regulating the MION or dextran concentration as well as the thermal incubation time, the sizes of these first formed nanoparticles (termed 1st-NPs) could be readily controlled. A second dextran coating step was further applied to smoothen the 1st-NPs in attaining a final product (termed 2nd-NPs). The 2nd-NPs exhibited robustly storage stability due to the additional coating shell. Results successfully confirmed the plausibility of this approach, as these MNPs displayed not only a smooth outline and a narrow size distribution, but also the essential superparamagnetic behavior and a significantly prolonged stability upon storage.
PMCID: PMC2818136  PMID: 19402138
superparamagnetic nanoparticle; size regulation; stable storage; double coating
16.  A biocompatible magnetic film: synthesis and characterization 
Biotechnology applications of magnetic gels include biosensors, targeted drug delivery, artificial muscles and magnetic buckles. These gels are produced by incorporating magnetic materials in the polymer composites.
A biocompatible magnetic gel film has been synthesized using polyvinyl alcohol. The magnetic gel was dried to generate a biocompatible magnetic film. Nanosized iron oxide particles (γ-Fe2O3, ~7 nm) have been used to produce the magnetic gel.
The surface morphology and magnetic properties of the gel films were studied. The iron oxide particles are superparamagnetic and the gel film also showed superparamagnetic behavior.
Magnetic gel made out of crosslinked magnetic nanoparticles in the polymer network was found to be stable and possess the magnetic properties of the nanoparticles.
PMCID: PMC373455  PMID: 14761251
17.  Surface engineering of iron oxide nanoparticles for targeted cancer therapy 
Accounts of chemical research  2011;44(10):853-862.
Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired biological response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy due to their intrinsic superparamagnetism that enables no-invasive magnetic resonance imaging (MRI) and biodegradability favorable for in vivo application. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and biological system, and a therapeutic payload that performs designated function in vivo. Often, a targeting ligand is also included in the design that recognizes the receptors over-expressed on cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the proper design of the iron oxide core to ensure MRI detectability and more critically, the coating to render the ability to bypass these barriers.
Strategies to bypass the physiological barriers such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells, and employing materials that promote desired intracellular trafficking and enable controlled drug release.
The payload can be genes, proteins, chemotherapy drugs, or a combination of them. Each therapeutic requires a specific coating design to maximize the loading and achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body’s defense system and provide examples of how these design parameters have been implemented to produce therapeutic SPIONs for specific therapeutic applications.
Although there are still challenges to be addressed, SPIONs show great promise in successful diagnosis and treatment of the most devastating cancers. Once critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as a truly multi-functional theranostic agent that not only performs a therapeutic function, but provides instant treatment feedback for the physician to adjust the treatment plan.
PMCID: PMC3192288  PMID: 21528865
18.  Magnetic nanoparticles: synthesis, functionalization, and applications in bioimaging and magnetic energy storage 
Chemical Society reviews  2009;38(9):2532-2542.
This tutorial review summarizes the recent advances in the chemical synthesis and potential applications of monodisperse magnetic nanoparticles. After a brief introduction to nanomagnetism, the review focuses on recent developments in solution phase syntheses of monodisperse MFe2O4, Co, Fe, CoFe, FePt and SmCo5 nanoparticles. The review further outlines the surface, structural, and magnetic properties of these nanoparticles for biomedicine and magnetic energy storage applications.
PMCID: PMC2740941  PMID: 19690734
19.  PEG-Mediated Synthesis of Highly Dispersive Multifunctional Superparamagnetic Nanoparticles: Their Physicochemical Properties and Function In Vivo 
ACS nano  2010;4(4):2402-2410.
Multifunctional superparamagnetic nanoparticles have been developed for a wide range of applications in nanomedicine, such as serving as tumor targeted drug carriers and molecular imaging agents. To function in vivo, the development of these novel materials must overcome several challenging requirements including biocompatibility, stability in physiological solutions, non-toxicity and the ability to traverse biological barriers. Here we report a PEG-mediated synthesis process to produce well-dispersed, ultrafine, and highly stable iron oxide nanoparticles for in vivo applications. Utilizing a biocompatible PEG coating bearing amine functional groups, the produced nanoparticles serve as an effective platform with the ability to incorporate a variety of targeting, therapeutic or imaging ligands. In this study, we demonstrated tumor-specific accumulation of these nanoparticles through both magnetic resonance and optical imaging after conjugation with chlorotoxin, a peptide with high affinity toward tumors of the neuroectodermal origin, and Cy5.5, a near-infrared fluorescent dye. Furthermore, we performed preliminary biodistribution and toxicity assessments of these nanoparticles in wild-type mice through histological analysis of clearance organs and hematology assay, and the results demonstrated the relative biocompatibility of these nanoparticles.
PMCID: PMC2860962  PMID: 20232826
iron oxide nanoparticle; nanomedicine; cancer; MRI; optical imaging; targeting; chlorotoxin; PEG
20.  Dextran Coated Ultrafine Superparamagnetic Iron Oxide Nanoparticles: Compatibility with Common Fluorometric and Colorimetric Dyes 
Analytical Chemistry  2011;83(10):3778-3785.
Due to the unique physicochemical properties of nanomaterials (NM) and their unknown reactivity, the possibility of NM altering the optical properties of fluorometric/colorimetric probes that are used to measure their cyto- and genotoxicity may lead to inaccurate readings. This could have potential implications given that NM, such as ultrafine superparamagnetic iron oxide nanoparticles (USPION), are increasingly finding their use in nanomedicine and the absorbance/fluorescence based assays are used to assess their toxicity. This study looks at the potential of dextran-coated USPION (dUSPION) (maghemite and magnetite) to alter the background signal of common probes used for evaluating cytotoxicity (MTS, CyQUANT, Calcein, and EthD-1) and oxidative stress (DCFH-DA and APF). In the present study, both forms of dUSPION caused an increase in MTS signal but a decrease in background signal from calcein and 3'-(p-aminophenyl) fluorescein (APF) and no effect on CyQUANT and EthD-1 fluorescence responses. Magnetite caused a decrease in fluorescence signal of DCFH, but it did not decrease fluorescence signal in the presence of the reactive oxygen species-inducer tert-butyl hydroperoxide (TBHP). In contrast, maghemite caused an increase in fluorescence, which was substantially reduced in the presence of the antioxidant N-acetyl cysteine. This study emphasizes the importance of considering and controlling for possible interactions between NM and fluorometric/colorimetric dyes and, most importantly, the oxidation state of dUSPION that may confound their sensitivity and specificity.
PMCID: PMC3095146  PMID: 21469681
21.  Synthesis, magnetic characterization and sensing applications of novel dextran-coated iron oxide nanorods 
Monodisperse, water-soluble dextran-coated iron oxide (Fe3O4) nanorods were synthesized using a facile and scalable approach. Our room temperature method involves the mixing of an acidic solution of iron salts with a basic solution of ammonium hydroxide to facilitate initial formation of iron oxide crystals. The stability, crystalinity and shape of these nanorods depends on the time of addition of the dextran, as well as the degree of purity of the polymer. The as-synthesized nanorods exhibit unique magnetic properties, including superparamagnetic behavior and high spin-spin water relaxivity (R2). Additionally, they possess enhanced peroxidase activity when compared to those reported in the literature for spherical iron oxide nanoparticles. Thus, this high yield synthetic method for polymer-coated iron oxide nanorods will expedite their use in applications from magnetic sensors, devices and nanocomposites with magnetic and catalytic properties.
PMCID: PMC2830002  PMID: 20204168
22.  Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications 
Superparamagnetic iron oxide nanoparticles can provide multiple benefits for biomedical applications in aqueous environments such as magnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality water-dispersible nanoparticles around 10 nm in size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.
Electronic supplementary material
The online version of this article (doi:10.1007/s11051-012-1100-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3460177  PMID: 23024598
Oleic acid-coated nanoparticles; Superparamagnetic; Surface modification; Silane; Colloidal stability; Iron oxide
23.  Biodistribution of newly synthesized PHEA-based polymer-coated SPION in Sprague Dawley rats as magnetic resonance contrast agent 
The purpose of this study was to observe the pharmacokinetic behavior of newly synthesized biocompatible polymers based on polyhydroxyethylaspartamide (PHEA) to be used to coat an iron oxide core to make superparamagnetic iron oxide nanoparticles (SPION).
Materials and methods
The isotopes [14C] and [59Fe] were used to label the polymer backbone (CLS) and iron oxide core (FLS), respectively. In addition, unradiolabeled cold superparamagnetic iron oxide nanoparticles (SPION/ULS) were synthesized to characterize particle size by dynamic light scattering, morphology by transmission electron microscopy, and in vivo magnetic resonance imaging (MRI). CLS and FLS were used separately to investigate the behavior of both the synthesized polymer and [Fe] in Sprague Dawley (SD) rats, respectively. Because radioactivity of the isotopes was different by β for CLS and γ for FLS, synthesis of the samples had to be separately prepared.
The mean particle size of the ULS was 66.1 nm, and the biodistribution of CLS concentrations in various organs, in rank order of magnitude, was liver > kidney > small intestine > other. The biodistribution of FLS concentrations was liver > spleen > lung > other. These rank orders show that synthesized SPION mainly accumulates in the liver. The differences in the distribution were caused by the SPION metabolism. Radiolabeled polymer was metabolized by the kidney and excreted mainly in the urine; [59Fe] was recycled for erythrocyte production in the spleen and excreted mainly in the feces. The MR image of the liver after intravenous injection demonstrated that [Fe] effectively accumulated in the liver and exhibited high-contrast enhancement on T2-weighted images.
This newly synthesized, polymer-coated SPION appears to be a promising candidate for use as a liver-targeted, biocompatible iron oxide MR imaging agent.
PMCID: PMC3817023  PMID: 24204138
SPION; radiolabeled; polyhydroxyethylaspartamide; pharmacokinetic; liver
24.  Multi-functional Magnetic Nanoparticles for Magnetic Resonance Imaging and Cancer Therapy 
Biomaterials  2010;32(7):1890-1905.
We have developed a multi-layer approach for the synthesis of water-dispersible superparamagnetic iron oxide nanoparticles for hyperthermia, magnetic resonance imaging (MRI) and drug delivery applications. In this approach, iron oxide core nanoparticles were obtained by precipitation of iron salts in the presence of ammonia and provided β-cyclodextrin and pluronic polymer (F127) coatings. This formulation (F127250) was highly water dispersible which allowed encapsulation of the anti-cancer drug(s) in β-cyclodextrin and pluronic polymer for sustained drug release. The F127250 formulation has exhibited superior hyperthermia effects over time under alternating magnetic field compared to pure magnetic nanoparticles (MNP) and β-cyclodextrin coated nanoparticles (CD200). Additionally, the improved MRI characteristics were also observed for the F127250 formulation in agar gel and in cisplatin resistant ovarian cancer cells (A12780CP) compared to MNP and CD200 formulations. Furthermore, the drug loaded formulation of F127250 exhibited many folds of imaging contrast properties. Due to the internalization capacity of the F127250 formulation, its curcumin loaded formulation (F127250-CUR) exhibited almost equivalent inhibition effects on A2780CP (ovarian), MDA-MB-231 (breast), and PC3 (prostate) cancer cells even though curcumin release was only 40%. The improved therapeutic effects were verified by examining molecular effects using Western blotting and transmission electron microscopic (TEM) studies. F127250-CUR also exhibited haemocompatibility, suggesting a nanochemo-therapuetic agent for cancer therapy.
PMCID: PMC3021632  PMID: 21167595
Magnetic nanoparticles; multi-layer coating; MRI; drug delivery; hyperthermia
25.  Gum Arabic-Coated Magnetic Nanoparticles for Potential Application in Simultaneous Magnetic Targeting and Tumor Imaging 
The AAPS Journal  2009;11(4):693-699.
Magnetic iron oxide nanoparticles (MNP) coated with gum arabic (GA), a biocompatible phytochemical glycoprotein widely used in the food industry, were successfully synthesized and characterized. GA-coated MNP (GA-MNP) displayed a narrow hydrodynamic particle size distribution averaging about 100 nm; a GA content of 15.6% by dry weight; a saturation magnetization of 93.1 emu/g Fe; and a superparamagnetic behavior essential for most magnetic-mediated applications. The GA coating offers two major benefits: it both enhances colloidal stability and provides reactive functional groups suitable for coupling of bioactive compounds. In vitro results showed that GA-MNP possessed a superior stability upon storage in aqueous media when compared to commercial MNP products currently used in magnetic resonance imaging (MRI). In addition, significant cellular uptake of GA-MNP was evaluated in 9L glioma cells by electron spin resonance (ESR) spectroscopy, fluorescence microscopy, and MRI analyses. Based on these findings, it was hypothesized that GA-MNP might be utilized as a MRI-visible drug carrier in achieving both magnetic tumor targeting and intracellular drug delivery. Indeed, preliminary in vivo investigations validate this clinical potential. MRI visually confirmed the accumulation of GA-MNP at the tumor site following intravenous administration to rats harboring 9L glioma tumors under the application of an external magnetic field. ESR spectroscopy quantitatively revealed a 12-fold increase in GA-MNP accumulation in excised tumors when compared to contralateral normal brain. Overall, the results presented show promise that GA-MNP could potentially be employed to achieve simultaneous tumor imaging and targeted intra-tumoral drug delivery.
PMCID: PMC2782085  PMID: 19842043
brain tumor; drug delivery; gum arabic; magnetic nanoparticle; magnetic targeting

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