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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.  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
3.  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
4.  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
5.  Immobilization on a Nanomagnetic Co/C Surface Using ROM Polymerization: Generation of a Hybrid Material as Support for a Recyclable Palladium Catalyst 
Advanced functional materials  2010;20(24):4323-4328.
A novel hybrid material is reported as support for a recyclable palladium catalyst via surface immobilization of a ligand onto Co-based magnetic nanoparticles (NPs). A standard “click” reaction is utilized to covalently attach a norbornene tag (Nb-tag) to the surface of the carbon coated cobalt NPs. The hybrid magnetic nanoparticles are produced by initiating polymerization of a mixture containing both Nb-tagged ligand (Nb-tagged PPh 3) and Nb-tagged carbon coated cobalt NPs. In turn, the norbornene units are suitably functionalized to serve as ligands for metal catalysts. A composite material is thus obtained which furnishes a loading that is one order of magnitude higher than the value obtained previously for the synthesis of functionalized Co/C-nanopowders. This allows for its application as a hybrid support with high local catalyst concentrations, as demonstrated for the immobilization of a highly active and recyclable palladium complex for Suzuki-Miyaura cross-coupling reactions. Due to the explicit magnetic moment of the cobalt- NPs, the overall magnetization of this organic/inorganic framework is significantly higher than of polymer coated iron oxide nanoparticles with comparable metal content, hence, its rapid separation from the reaction mixture and recycling via an external magnetic field is not hampered by the functionalized polymer shell.
doi:10.1002/adfm.201000959
PMCID: PMC3271946  PMID: 22308111
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.  Technogenic Magnetic Particles in Alkaline Dusts from Power and Cement Plants 
Water, Air, and Soil Pollution  2012;224(1):1389.
During this study, we investigated the mineralogical characterization of technogenic magnetic particles (TMPs) contained in alkaline industrial dust and fly ash emitted by coal burning power plants and cement plants. The reaction of tested dust samples varied between values of pH 8 and pH 12. Their magnetic properties were characterized by measurement of magnetic susceptibility (χ), frequency dependence of magnetic susceptibility (χfd), and temperature dependence of magnetic susceptibility. Mineralogical and geochemical analyses included scanning electron microscopy with energy dispersive spectroscopy, microprobe analysis and X-ray diffraction. The TMPs in fly ash from hard coal combustion have the form of typical magnetic spherules with a smooth or corrugated surface as well as a skeletal morphology, composed of iron oxides (magnetite, maghemite, and magnesioferrite) that occurred in the form of incrustation on the surface of mullite, amorphous silica, or aluminosilicate particles. The TMPs observed in fly ash from lignite combustion have a similar morphological form but a different mineralogical composition. Instead of magnetite and magnesioferrite, maghemite and hematite with lower χ values were the prevailing magnetic minerals, which explains the much lower magnetic susceptibility of this kind of ash in comparison with the ash from hard coal combustion, and probably results from the lower temperature of lignite combustion. Morphology and mineralogical composition of TMPs in cement dust is more diverse. The magnetic fraction of cement dust occurs mostly in the form of angular and octahedral grains of a significantly finer granulation (<20 μm); however, spherules are also present. A very characteristic magnetic form for cement dust is calcium ferrite (CaFe3O5). The greatest impact on the magnetic susceptibility of cement dust results from iron-bearing additives (often waste materials from other branches of industry), which should be considered the most dangerous to the environment. Stoichiometric analysis of micro-particles confirmed the presence of heavy metals such as Pb, Mn, Cd, and Zn connected with TMPs, which are carriers of magnetic signals in atmospheric dust. Therefore, in some cases, their presence in topsoil when detected by magnetic measurement can be treated as an indicator of inorganic soil contamination.
doi:10.1007/s11270-012-1389-9
PMCID: PMC3543769  PMID: 23325986
Alkaline dusts; Magnetic susceptibility; Technogenic magnetic particles; Iron mineralogy
8.  Nanoscale Metal–Organic Frameworks for Biomedical Imaging and Drug Delivery 
Accounts of chemical research  2011;44(10):957-968.
CONSPECTUS
Metal–organic frameworks (MOFs), a class of hybrid materials formed by the self-assembly of polydentate bridging ligands and metal-connecting points, have been studied for a variety of applications. Recently, these materials have been scaled down to nanometer sizes, and this Account details the development of nanoscale metal–organic frameworks (NMOFs) for biomedical applications. NMOFs possess several potential advantages over conventional nanomedicines such as their structural and chemical diversity, their high loading capacity, and their intrinsic biodegradability. Under relatively mild conditions, NMOFs can be obtained as either crystalline or amorphous materials. The particle composition, size, and morphology can be easily tuned to optimize the final particle properties. Researchers have employed two general strategies to deliver active agents using NMOFs: by incorporating active agents into the frameworks or by loading active agents into the pores and channels of the NMOFs. The modification of NMOF surfaces with either silica coatings or organic polymers improves NMOF stability, fine-tunes their properties, and imparts additional functionality.
Preliminary biomedical applications of NMOFs have focused on their use as delivery vehicles for imaging contrast agents and molecular therapeutics. Because NMOFs can carry large amounts of paramagnetic metal ions, they have been extensively explored as magnetic resonance imaging (MRI) contrast agents. Both Gd3+- and Mn2+-containing NMOFs have shown excellent efficacy as T1-weighted contrast agents with large per metal- and per particle-based MR relaxivities. Fe3+-containing NMOFs have demonstrated excellent T2-weighted contrast enhancement. Upon intravenous injection of iron carboxylate NMOFs in Wistar rats, researchers observed negative signal enhancement in the liver and spleen, which dissipated over time, indicating the degradation and clearance of the NMOF. Through the incorporation of luminescent or high Z element building blocks, NMOFs have also served as viable contrast agents for optical imaging or X-ray computed tomography (CT) imaging. Incorporation of membrane impermeable dyes into NMOFs allowed for their uptake by cancer cells and for their controlled release as the framework decomposed.
NMOFs have been used to deliver anticancer drugs and other chemotherapeutics. Cisplatin prodrugs were incorporated within NMOFs at exceptionally high levels, either through use of the prodrug as the building block or through attachment of the prodrug onto the framework after synthesis. These NMOFs were encapsulated within a silica shell and targeted to cancer cells. In vitro assays revealed that the targeted NMOFs possessed similar efficacy to cisplatin, while the nontargeted NMOFs were less active. Several different therapeutic molecules were loaded within porous iron-carboxylate NMOFs at unprecedented levels. The NMOF showed sustained drug release with no burst effect, and in vitro assays revealed that the nanoencapsulated drug possessed similar efficacy to the free drug. Although still at a very early stage of development, NMOFs have already shown great promise as a novel platform for nanomedicine. The compositional tunability and mild synthetic conditions used to produce NMOFs should allow for the incorporation of other imaging and therapeutic agents and their effective delivery to targeted cells in vivo.
doi:10.1021/ar200028a
PMCID: PMC3777245  PMID: 21648429
9.  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
10.  Poly-l-lysine-coated magnetic nanoparticles as intracellular actuators for neural guidance 
Purpose
It has been proposed in the literature that Fe3O4 magnetic nanoparticles (MNPs) could be exploited to enhance or accelerate nerve regeneration and to provide guidance for regenerating axons. MNPs could create mechanical tension that stimulates the growth and elongation of axons. Particles suitable for this purpose should possess (1) high saturation magnetization, (2) a negligible cytotoxic profile, and (3) a high capacity to magnetize mammalian cells. Unfortunately, the materials currently available on the market do not satisfy these criteria; therefore, this work attempts to overcome these deficiencies.
Methods
Magnetite particles were synthesized by an oxidative hydrolysis method and characterized based on their external morphology and size distribution (high-resolution transmission electron microscopy [HR-TEM]) as well as their colloidal (Z potential) and magnetic properties (Superconducting QUantum Interference Devices [SQUID]). Cell viability was assessed via Trypan blue dye exclusion assay, cell doubling time, and MTT cell proliferation assay and reactive oxygen species production. Particle uptake was monitored via Prussian blue staining, intracellular iron content quantification via a ferrozine-based assay, and direct visualization by dual-beam (focused ion beam/scanning electron microscopy [FIB/SEM]) analysis. Experiments were performed on human neuroblastoma SH-SY5Y cell line and primary Schwann cell cultures of the peripheral nervous system.
Results
This paper reports on the synthesis and characterization of polymer-coated magnetic Fe3O4 nanoparticles with an average diameter of 73 ± 6 nm that are designed as magnetic actuators for neural guidance. The cells were able to incorporate quantities of iron up to 2 pg/cell. The intracellular distribution of MNPs obtained by optical and electronic microscopy showed large structures of MNPs crossing the cell membrane into the cytoplasm, thus rendering them suitable for magnetic manipulation by external magnetic fields. Specifically, migration experiments under external magnetic fields confirmed that these MNPs can effectively actuate the cells, thus inducing measurable migration towards predefined directions more effectively than commercial nanoparticles (fluidMAG-ARA supplied by Chemicell). There were no observable toxic effects from MNPs on cell viability for working concentrations of 10 μg/mL (EC25 of 20.8 μg/mL, compared to 12 μg/mL in fluidMAG-ARA). Cell proliferation assays performed with primary cell cultures of the peripheral nervous system confirmed moderate cytotoxicity (EC25 of 10.35 μg/mL).
Conclusion
These results indicate that loading neural cells with the proposed MNPs is likely to be an effective strategy for promoting non-invasive neural regeneration through cell magnetic actuation.
doi:10.2147/IJN.S28460
PMCID: PMC3394465  PMID: 22811603
magnetic nanoparticle; actuator; migration; neural regeneration
11.  Magnetic and optical properties of multifunctional core-shell radioluminescence nanoparticles 
Journal of materials chemistry  2012;22(25):12802-12809.
When X-rays irradiate radioluminescence nanoparticles, they generate visible and near infrared light that can penetrate through centimeters of tissue. X-ray luminescence tomography (XLT) maps the location of these radioluminescent contrast agents at high resolution by scanning a narrow X-ray beam through the tissue sample and collecting the luminescence at every position. Adding magnetic functionality to these radioluminescent particles would enable them to be guided, oriented, and heated using external magnetic fields, while their location and spectrum could be imaged with XLT and complementary magnetic resonance imaging. In this work, multifunctional monodispersed magnetic radioluminescent nanoparticles were developed as potential drug delivery carriers and radioluminescence imaging agents. The particles consisted of a spindle-shaped magnetic γ-Fe2O3 core and a radioluminescent europium-doped gadolinium oxide shell. Particles with solid iron oxide cores displayed saturation magnetizations consistent with their ~13% core volume, however, the iron oxide quenched their luminescence. In order to increase the luminescence, we partially etched the iron oxide core in oxalic acid while preserving the radioluminescent shell. The core size was controlled by the etching time which in turn affected the particles’ luminescence and magnetic properties. Particles with intermediate core sizes displayed both strong magnetophoresis and luminescence properties. They also served as MRI contrast agents with relaxivities of up to 58 mM−1s−1 (r2) and 120 mM−1s−1 (r2*). These particles offer promising multimodal MRI/fluorescence/X-ray luminescence contrast agents. Our core-shell synthesis technique offers a flexible method to control particle size, shape, and composition for a wide range of biological applications of magnetic/luminescent nanoparticles.
doi:10.1039/C2JM15444G
PMCID: PMC3918467  PMID: 24520183
12.  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
13.  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
14.  Preparation, Characterization, and Application of Magnetic Fe-SBA-15 Mesoporous Silica Molecular Sieves 
Magnetic Fe-SBA-15 mesoporous silica molecular sieves were prepared, characterized, and used for magnetic separation. Wet impregnation, drying, and calcination steps led to iron inclusion within the mesopores. Iron oxide was reduced to the metal form with hydrogen, and the magnetic Fe-SBA-15 was obtained. Fourier-transform infrared spectroscopy confirmed the preparation process from the oxide to metal forms. The structure of magnetic materials was confirmed by Mössbauer spectra. Powder X-ray diffraction data indicated that the structure of Fe-SBA-15 retained the host SBA-15 structure. Brunauer-Emmett-Teller analysis revealed a decrease in surface area and pore size, indicating Fe-SBA-15 coating on the inner surfaces. Scanning electron micrographs confirmed the decrease in size for modified SBA-15 particles. From scanning electron micrographs, it was found that the size of the modified SBA-15 particles decreased. Transmission electron micrographs also confirmed that modified SBA-15 retained the structure of the parent SBA-15 silica. Fe-SBA-15 exhibited strong magnetic properties, with a magnetization value of 8.8 emu g−1. The iron content in Fe-SBA-15 was determined by atom adsorption spectroscopy. Fe-SBA-15 was successfully used for the magnetic separation of three aromatic compounds in water. Our results suggest wide applicability of Fe-SBA-15 magnetic materials for the rapid and efficient separation of various compounds.
doi:10.1155/2010/323509
PMCID: PMC2997508  PMID: 21151665
15.  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
16.  Development of Novel Magnetic Nanoparticles for Hyperthermia Cancer Therapy 
Proceedings of SPIE  2011;7901:790115-.
Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe3O4) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe3O4 with superior SAR values.
doi:10.1117/12.876514
PMCID: PMC3947375  PMID: 24619487
Magnetic Nanoparticle; Ferrofluid; Hyperthermia; Tumor; Cancer; Synthesis
17.  Surface engineering of iron oxide nanoparticles for targeted cancer therapy 
Accounts of chemical research  2011;44(10):853-862.
Conspectus
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.
doi:10.1021/ar2000277
PMCID: PMC3192288  PMID: 21528865
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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