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1.  A biocompatible magnetic film: synthesis and characterization 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1477-044X-2-2
PMCID: PMC373455  PMID: 14761251
2.  Inorganic Nanoparticles for Multimodal Molecular Imaging 
Molecular imaging  2011;10(1):3-16.
Multimodal molecular imaging can offer a synergistic improvement of diagnostic ability over a single imaging modality. Recent development of hybrid imaging systems has profoundly impacted the pool of available multimodal imaging probes. In particular, much interest has been focused on biocompatible, inorganic nanoparticle–based multimodal probes. Inorganic nanoparticles offer exceptional advantages to the field of multimodal imaging owing to their unique characteristics, such as nanometer dimensions, tunable imaging properties, and multifunctionality. Nanoparticles mainly based on iron oxide, quantum dots, gold, and silica have been applied to various imaging modalities to characterize and image specific biologic processes on a molecular level. A combination of nanoparticles and other materials such as biomolecules, polymers, and radiometals continue to increase functionality for in vivo multimodal imaging and therapeutic agents. In this review, we discuss the unique concepts, characteristics, and applications of the various multimodal imaging probes based on inorganic nanoparticles.
PMCID: PMC3629957  PMID: 21303611
3.  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
4.  Surface Engineering of Core/Shell Iron/Iron Oxide Nanoparticles from Microemulsions for Hyperthermia 
This paper describes the synthesis and surface engineering of core/shell-type iron/iron oxide nanoparticles for magnetic hyperthermia cancer therapy. Iron/iron oxide nanoparticles were synthesized from microemulsions of NaBH4 and FeCl3, followed by surface modification in which a thin hydrophobic hexamethyldisilazane layer - used to protect the iron core - replaced the CTAB coating on the particles. Phosphatidylcholine was then assembled on the nanoparticle surface. The resulting nanocomposite particles have a biocompatible surface and show good stability in both air and aqueous solution. Compared to iron oxide nanoparticles, the nanocomposites show much better heating in an alternating magnetic field. They are good candidates for both hyperthermia and magnetic resonance imaging applications.
doi:10.1016/j.msec.2009.09.003
PMCID: PMC3151654  PMID: 21833157
5.  Nanotoxicology and nanoparticle safety in biomedical designs 
Nanotechnology has wide applications in many fields, especially in the biological sciences and medicine. Nanomaterials are applied as coating materials or in treatment and diagnosis. Nanoparticles such as titania, zirconia, silver, diamonds, iron oxides, carbon nanotubes, and biodegradable polymers have been studied in diagnosis and treatment. Many of these nanoparticles may have toxic effects on cells. Many factors such as size, inherent properties, and surface chemistry may cause nanoparticle toxicity. There are methods for improving the performance and reducing toxicity of nanoparticles in medical design, such as biocompatible coating materials or biodegradable/biocompatible nanoparticles. Most metal oxide nanoparticles show toxic effects, but no toxic effects have been observed with biocompatible coatings. Biodegradable nanoparticles are also used in the efficient design of medical materials, which will be reviewed in this article.
doi:10.2147/IJN.S16603
PMCID: PMC3118686  PMID: 21698080
nanotechnology; nanotoxicology; nanomaterials; nanobiomaterials
6.  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.
doi:10.1088/0957-4484/21/17/175704
PMCID: PMC2859998  PMID: 20368682
7.  Surface Functionalization of Magnetic Iron Oxide Nanoparticles for MRI Applications – Effect of Anchoring Group and Ligand Exchange Protocol 
Hydrophobic magnetite nanoparticles synthesized from thermal decomposition of iron salts must be rendered hydrophilic for their application as MRI contrast agents. This process requires refunctionalizing the surface of the nanoparticles with a hydrophilic organic coating such as polyethylene glycol. Two parameters were found to influence the magnetic behavior and relaxivity of the resulting hydrophilic iron oxide nanoparticles: the functionality of the anchoring group and the protocol followed for the functionalization. Nanoparticles coated with PEGs via a catecholate-type anchoring moiety maintain the saturation magnetization and relaxivity of the hydrophobic magnetite precursor. Other anchoring functionalities, such as phosphonate, carboxylate, and dopamine decrease the magnetization and relaxivity of the contrast agent. The protocol for functionalizing the nanoparticles also influences the magnetic behavior of the material. Nanoparticles refunctionalized according to a direct biphasic protocol exhibit higher relaxivity than those refunctionalized according to a two-step procedure which first involves stripping the nanoparticles. This research presents the first systematic study of both the binding moiety and the functionalization protocol on the relaxivity and magnetization of water-soluble coated iron oxide nanoparticles used as MRI contrast agents.
doi:10.1002/cmmi.417
PMCID: PMC3123420  PMID: 21861279
MRI; contrast agent; MION; iron oxide nanoparticles; superparamagnetic agents; surface functionalization; relaxivity; magnetism
8.  Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy 
Theranostics  2012;2(1):3-44.
Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications.
doi:10.7150/thno.3463
PMCID: PMC3263514  PMID: 22272217
Multifunctional nanoparticles; magnetic nanoparticles; targeting ligand; bioconjugation; surface engineering; long circulation
9.  Bcl-2-functionalized ultrasmall superparamagnetic iron oxide nanoparticles coated with amphiphilic polymer enhance the labeling efficiency of islets for detection by magnetic resonance imaging 
Based on their versatile, biocompatible properties, superparamagnetic iron oxide (SPIO) or ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are utilized for detecting and tracing cells or tumors in vivo. Here, we developed an innoxious and concise synthesis approach for a novel B-cell lymphoma (Bcl)-2 monoclonal antibody-functionalized USPIO nanoparticle coated with an amphiphilic polymer (carboxylated polyethylene glycol monooleyl ether [OE-PEG-COOH]). These nanoparticles can be effectively internalized by beta cells and label primary islet cells, at relatively low iron concentration. The biocompatibility and cytotoxicity of these products were investigated by comparison with the commercial USPIO product, FeraSpin™ S. We also assessed the safe dosage range of the product. Although some cases showed a hypointensity change at the site of transplant, a strong magnetic resonance imaging (MRI) was detectable by a clinical MRI scanner, at field strength of 3.0 Tesla, in vivo, and the iron deposition/attached in islets was confirmed by Prussian blue and immunohistochemistry staining. It is noteworthy that based on our synthesis approach, in future, we could exchange the Bcl-2 with other probes that would be more specific for the targeted cells and that would have better labeling specificity in vivo. The combined results point to the promising potential of the novel Bcl-2-functionalized PEG-USPIO as a molecular imaging agent for in vivo monitoring of islet cells or other cells.
doi:10.2147/IJN.S52058
PMCID: PMC3804583  PMID: 24204136
USPIO; MRI; beta cells; nanoparticle functionalization; islet transplantation; cell tracing
10.  Biocompatibility of Polymer Grafted Core/Shell Iron/Carbon Nanoparticles 
Biomaterials  2010;31(19):5083-5090.
For biomedical applications, emerging nanostructures requires stringent evaluations for their biocompatibility. Core/shell iron/carbon nanoparticles (Fe@CNPs) are nanomaterials that have potential applications in magnetic resonance imaging (MRI), magnetic hyperthermia and drug delivery. However, their interactions with biological systems are totally unknown. To evaluate their potential cellular perturbations and explore the relationships between their biocompatibility and surface chemistry, we synthesized polymer grafted Fe@CNPs with diverse chemistry modifications on surface and investigated their dynamic cellular responses, cell uptake, oxidative stress and their effects on cell apoptosis and cell cycle. The results show that biocompatibility of Fe@CNPs is both surface chemistry dependent and cell type specific. Except for the carboxyl modified Fe@CNPs, all other Fe@CNPs present low toxicity and can be used for further functionalization and in a wide range of biomedical applications.
doi:10.1016/j.biomaterials.2010.03.020
PMCID: PMC2867056  PMID: 20378165
nanomaterials; core/shell nanoparticles; biocompatibility; RT-CES; cytotoxicity
11.  Biodistribution of newly synthesized PHEA-based polymer-coated SPION in Sprague Dawley rats as magnetic resonance contrast agent 
Objectives
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.
Results
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.
Conclusion
This newly synthesized, polymer-coated SPION appears to be a promising candidate for use as a liver-targeted, biocompatible iron oxide MR imaging agent.
doi:10.2147/IJN.S51684
PMCID: PMC3817023  PMID: 24204138
SPION; radiolabeled; polyhydroxyethylaspartamide; pharmacokinetic; liver
12.  Iron Oxide Nanoparticle-Micelles (ION-Micelles) for Sensitive (Molecular) Magnetic Particle Imaging and Magnetic Resonance Imaging 
PLoS ONE  2013;8(2):e57335.
Background
Iron oxide nanoparticles (IONs) are a promising nanoplatform for contrast-enhanced MRI. Recently, magnetic particle imaging (MPI) was introduced as a new imaging modality, which is able to directly visualize magnetic particles and could serve as a more sensitive and quantitative alternative to MRI. However, MPI requires magnetic particles with specific magnetic properties for optimal use. Current commercially available iron oxide formulations perform suboptimal in MPI, which is triggering research into optimized synthesis strategies. Most synthesis procedures aim at size control of iron oxide nanoparticles rather than control over the magnetic properties. In this study, we report on the synthesis, characterization and application of a novel ION platform for sensitive MPI and MRI.
Methods and Results
IONs were synthesized using a thermal-decomposition method and subsequently phase-transferred by encapsulation into lipidic micelles (ION-Micelles). Next, the material and magnetic properties of the ION-Micelles were analyzed. Most notably, vibrating sample magnetometry measurements showed that the effective magnetic core size of the IONs is 16 nm. In addition, magnetic particle spectrometry (MPS) measurements were performed. MPS is essentially zero-dimensional MPI and therefore allows to probe the potential of iron oxide formulations for MPI. ION-Micelles induced up to 200 times higher signal in MPS measurements than commercially available iron oxide formulations (Endorem, Resovist and Sinerem) and thus likely allow for significantly more sensitive MPI. In addition, the potential of the ION-Micelle platform for molecular MPI and MRI was showcased by MPS and MRI measurements of fibrin-binding peptide functionalized ION-Micelles (FibPep-ION-Micelles) bound to blood clots.
Conclusions
The presented data underlines the potential of the ION-Micelle nanoplatform for sensitive (molecular) MPI and warrants further investigation of the FibPep-ION-Micelle platform for in vivo, non-invasive imaging of fibrin in preclinical disease models of thrombus-related pathologies and atherosclerosis.
doi:10.1371/journal.pone.0057335
PMCID: PMC3577714  PMID: 23437371
13.  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
14.  Hybrid gold-iron oxide nanoparticles as a multifunctional platform for biomedical application 
Background
Iron oxide nanoparticles (IONPs) have increasing applications in biomedicine, however fears over long term stability of polymer coated particles have arisen. Gold coating IONPs results in particles of increased stability and robustness. The unique properties of both the iron oxide (magnetic) and gold (surface plasmon resonance) result in a multimodal platform for use as MRI contrast agents and as a nano-heater.
Results
Here we synthesize IONPs of core diameter 30 nm and gold coat using the seeding method with a poly(ethylenimine) intermediate layer. The final particles were coated in poly(ethylene glycol) to ensure biocompatibility and increase retention times in vivo. The particle coating was monitored using FTIR, PCS, UV–vis absorption, TEM, and EDX. The particles appeared to have little cytotoxic effect when incubated with A375M cells. The resultant hybrid nanoparticles (HNPs) possessed a maximal absorbance at 600 nm. After laser irradiation in agar phantom a ΔT of 32°C was achieved after only 90 s exposure (50 μgmL-1). The HNPs appeared to decrease T2 values in line with previously clinically used MRI contrast agent Feridex®.
Conclusions
The data highlights the potential of these HNPs as dual function MRI contrast agents and nano-heaters for therapies such as cellular hyperthermia or thermo-responsive drug delivery.
doi:10.1186/1477-3155-10-27
PMCID: PMC3448509  PMID: 22731703
Magnetic nanoparticles; Gold nano-shells; Magnetic resonance imaging; Surface plasmon resonance; Multifunctional nanoparticles
15.  Synthesis and characterization of ultra-small superparamagnetic iron oxide nanoparticles thinly coated with silica 
Nanotechnology  2008;19(33):335601.
Ultra-small superparamagnetic iron oxide nanoparticles (SPIOs) were synthesized by co-precipitation of iron chloride salts with ammonia and then encapsulated with thin (~2nm) layers of silica. The particles have been characterized for size, diffraction pattern, surface charge, and magnetic properties. This rapid and economical synthesis has a number of industrial applications; however, the silica-coated particles have been optimized for use in medical applications as MR contrast agents, biosensors, DNA capturing, bioseparation and enzyme immobilization
doi:10.1088/0957-4484/19/33/335601
PMCID: PMC2600798  PMID: 19701448
16.  Nanoclusters of iron oxide: effect of core composition on structure, biocompatibility and cell labeling efficacy 
Bioconjugate chemistry  2012;23(5):941-950.
Inorganic nanocrystals have a variety of applications in medicine. They may serve as contrast agents, therapeutics and for in vitro diagnostics. Frequently, the synthesis route yields hydrophobically capped nanocrystals, which necessitates their subsequent coating to render a water-soluble and biocompatible probe. Biocompatibility is crucial for cellular imaging applications, which require large quantities of diagnostically active nanoparticles to be loaded into cells. We have previously reported the design and synthesis of a fluorescent and magnetic resonance imaging-detectable core-shell nanoparticle that encapsulates hydrophobically coated iron oxide nanocrystals. The core of soybean oil and iron oxide is covered by a shell mixture of phospholipids, some of which contained polyethylene glycol. Despite the biocompatibility of these components, we hypothesize that we can improve this formulation with respect to in vitro toxicity. To this aim, we measured the effect of six different core compositions on nanoparticle structure, cell labeling efficacy and cell viability, as well as cell tracking potential. We methodically investigated the causes of toxicity and conclude that, even when combining biocompatible materials, the resulting formulation is not guaranteed to be biocompatible.
doi:10.1021/bc200543k
PMCID: PMC3419767  PMID: 22471239
MRI; fluorescence; nanoparticle; cytotoxicity
17.  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.
doi:10.1021/nn100190v
PMCID: PMC2860962  PMID: 20232826
iron oxide nanoparticle; nanomedicine; cancer; MRI; optical imaging; targeting; chlorotoxin; PEG
18.  Multifunctional Magnetic Nanoparticles for Medical Imaging Applications 
Journal of materials chemistry  2009;19:6258-6266.
Magnetic nanoparticles (MNPs) have attracted enormous research attention due to their unique magnetic properties that enable the detection by the non-invasive medical imaging modality—magnetic resonance imaging (MRI). By incorporating advanced features, such as specific targeting, multimodality, therapeutic delivery, the detectability and applicability of MNPs have been dramatically expanded. A delicate design on structure, composition and surface chemistry is essential to achieving desired properties in MNP systems, such as high imaging contrast and chemical stability, non-fouling surface, target specificity and/or multimodality. This article presents the design fundamentals on the development of MNP systems, from discussion of material selection for nanoparticle cores and coatings, strategies for chemical synthesis and surface modification and their merits and limitations, to conjugation of special biomolecules for intended functions, and reviews the recent advances in the field.
doi:10.1039/b902182e
PMCID: PMC2893338  PMID: 20593005
19.  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.
doi:10.3390/ijms140917501
PMCID: PMC3794737  PMID: 24065092
Feraheme; magnetic fluid hyperthermia; magnetic nanoparticles; MRI contrast
20.  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.
doi:10.1007/s11095-012-0679-7
PMCID: PMC3734862  PMID: 22274558
cancer; diagnosis; drug delivery; gene delivery; iron oxide nanoparticle; magnetic nanoparticle; molecular imaging; MRI; nanomedicine; siRNA; therapy
21.  Cytotoxicity of iron oxide nanoparticles made from the thermal decomposition of organometallics and aqueous phase transfer with Pluronic F127 
Magnetic nanoparticles are promising molecular imaging agents due to their relative high relaxivity and the potential to modify surface functionality to tailor biodistribution. In this work we describe the synthesis of magnetic nanoparticles using organic solvents with organometallic precursors. This method results in nanoparticles that are highly crystalline, and have uniform size and shape. The ability to create a monodispersion of particles of the same size and shape results in unique magnetic properties that can be useful for biomedical applications with MR imaging. Before these nanoparticles can be used in biological applications, however, means are needed to make the nanoparticles soluble in aqueous solutions and the toxicity of these nanoparticles needs to be studied.
We have developed two methods to surface modify and transfer these nanoparticles to the aqueous phase using the biocompatible co-polymer, Pluronic F127. Cytotoxicity was found to be dependent on the coating procedure used. Nanoparticle effects on a cell-culture model was quantified using concurrent assaying; a LDH assay to determine cytotoxicity and an MTS assay to determine viability for a 24 hour incubation period. Concurrent assaying was done to insure that nanoparticles did not interfere with the colorimetric assay results.
This report demonstrates that a monodispersion of nanoparticles of uniform size and shape can be manufactured. Initial cytotoxicity testing of new molecular imaging agents need to be carefully constructed to avoid interference and erroneous results.
doi:10.1002/cmmi.391
PMCID: PMC3020093  PMID: 20623517
MRI; molecular imaging; nanoparticles; superparamagnetic agents; cytotoxicity; Colorimetric Assay; Pluronics
22.  Preparation and Characterization of Ferrofluid Stabilized with Biocompatible Chitosan and Dextran Sulfate Hybrid Biopolymer as a Potential Magnetic Resonance Imaging (MRI) T2 Contrast Agent 
Marine Drugs  2012;10(11):2403-2414.
Chitosan is the deacetylated form of chitin and used in numerous applications. Because it is a good dispersant for metal and/or oxide nanoparticle synthesis, chitosan and its derivatives have been utilized as coating agents for magnetic nanoparticles synthesis, including superparamagnetic iron oxide nanoparticles (SPIONs). Herein, we demonstrate the water-soluble SPIONs encapsulated with a hybrid polymer composed of polyelectrolyte complexes (PECs) from chitosan, the positively charged polymer, and dextran sulfate, the negatively charged polymer. The as-prepared hybrid ferrofluid, in which iron chloride salts (Fe3+ and Fe2+) were directly coprecipitated inside the hybrid polymeric matrices, was physic-chemically characterized. Its features include the z-average diameter of 114.3 nm, polydispersity index of 0.174, zeta potential of −41.5 mV and iron concentration of 8.44 mg Fe/mL. Moreover, based on the polymer chain persistence lengths, the anionic surface of the nanoparticles as well as the high R2/R1 ratio of 13.5, we depict the morphology of SPIONs as a cluster because chitosan chains are chemisorbed onto the anionic magnetite surfaces by tangling of the dextran sulfate. Finally, the cellular uptake and biocompatibility assays indicate that the hybrid polymer encapsulating the SPIONs exhibited great potential as a magnetic resonance imaging T2 contrast agent for cell tracking.
doi:10.3390/md10112403
PMCID: PMC3509525  PMID: 23203267
biocompatible polymer; chitosan; superparamagnetic iron oxide nanoparticle; nanomaterials
23.  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
24.  Inorganic nanoparticle-based contrast agents for molecular imaging 
Trends in molecular medicine  2010;16(12):561-573.
Inorganic nanoparticles including semiconductor quantum dots, iron oxide nanoparticles, and gold nanoparticles have been developed as contrast agents for diagnostics by molecular imaging. Compared to traditional contrast agents, nanoparticles offer several advantages: their optical and magnetic properties can be tailored by engineering the composition, structure, size, and shape; their surfaces can be modified with ligands to target specific biomarkers of disease; the contrast enhancement provided can be equivalent to millions of molecular counterparts; and they can be integrated with a combination of different functions for multi-modal imaging. Here, we review recent advances in the development of contrast agents based on inorganic nanoparticles for molecular imaging, with a touch on contrast enhancement, surface modification, tissue targeting, clearance, and toxicity. As research efforts intensify, contrast agents based on inorganic nanoparticles that are highly sensitive, target-specific, and safe to use are expected to enter clinical applications in the near future.
doi:10.1016/j.molmed.2010.09.004
PMCID: PMC3052982  PMID: 21074494
25.  Influence of the Physiochemical Properties of Superparamagnetic Iron Oxide Nanoparticles on Amyloid β Protein Fibrillation in Solution 
ACS Chemical Neuroscience  2012;4(3):475-485.
Superparamagnetic iron oxide nanoparticles (SPIONs) are recognized as promising nanodiagnostic materials due to their biocompatibility, unique magnetic properties, and their application as multimodal contrast agents. As coated SPIONs have potential use in the diagnosis and treatment of various brain diseases such as Alzheimer’s, a comprehensive understanding of their interactions with Aβ and other amyloidogenic proteins is essential prior to their clinical application. Here we demonstrate the effect of thickness and surface charge of the coating layer of SPIONs on the kinetics of fibrillation of Aβ in aqueous solution. A size and surface area dependent “dual” effect on Aβ fibrillation was observed. While lower concentrations of SPIONs inhibited fibrillation, higher concentrations increased the rate of Aβ fibrillation. With respect to coating charge, it is evident that the positively charged SPIONs are capable of promoting fibrillation at significantly lower particle concentrations compared with negatively charged or uncharged SPIONs. This suggests that in addition to the presence of particles, which affect the concentration of monomeric protein in solution (and thereby the nucleation time), there are also effects of binding on the protein conformation.
doi:10.1021/cn300196n
PMCID: PMC3605812  PMID: 23509983
Superparamagnetic iron oxide nanoparticles; Alzheimer’s disease; amyloid beta; fibrillation; protein conformation

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