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1.  Structural properties of magnetic nanoparticles determine their heating behavior - an estimation of the in vivo heating potential 
Nanoscale Research Letters  2014;9(1):602.
Magnetically induced heating of magnetic nanoparticles (MNP) in an alternating magnetic field (AMF) is a promising minimally invasive tool for localized tumor treatment by sensitizing or killing tumor cells with the help of thermal stress. Therefore, the selection of MNP exhibiting a sufficient heating capacity (specific absorption rate, SAR) to achieve satisfactory temperatures in vivo is necessary. Up to now, the SAR of MNP is mainly determined using ferrofluidic suspensions and may distinctly differ from the SAR in vivo due to immobilization of MNP in tissues and cells. The aim of our investigations was to study the correlation between the SAR and the degree of MNP immobilization in dependence of their physicochemical features.
In this study, the included MNP exhibited varying physicochemical properties and were either made up of single cores or multicores. Whereas the single core MNP exhibited a core size of approximately 15 nm, the multicore MNP consisted of multiple smaller single cores (5 to 15 nm) with 65 to 175 nm diameter in total. Furthermore, different MNP coatings, including dimercaptosuccinic acid (DMSA), polyacrylic acid (PAA), polyethylenglycol (PEG), and starch, wereinvestigated. SAR values were determined after the suspension of MNP in water. MNP immobilization in tissues was simulated with 1% agarose gels and 10% polyvinyl alcohol (PVA) hydrogels.
The highest SAR values were observed in ferrofluidic suspensions, whereas a strong reduction of the SAR after the immobilization of MNP with PVA was found. Generally, PVA embedment led to a higher immobilization of MNP compared to immobilization in agarose gels. The investigated single core MNP exhibited higher SAR values than the multicore MNP of the same core size within the used magnetic field parameters. Multicore MNP manufactured via different synthesis routes (fluidMAG-D, fluidMAG/12-D) showed different SAR although they exhibited comparable core and hydrodynamic sizes. Additionally, no correlation between ζ-potential and SAR values after immobilization was observed.
Our data show that immobilization of MNP, independent of their physicochemical properties, can distinctly affect their SAR. Similar processes are supposed to take place in vivo, particularly when MNP are immobilized in cells and tissues. This aspect should be adequately considered when determining the SAR of MNP for magnetic hyperthermia.
doi:10.1186/1556-276X-9-602
PMCID: PMC4230907  PMID: 25404872
Immobilization; Specific absorption rate (SAR); Intrinsic loss power (ILP); Magnetic nanoparticles (MNP); Magnetic hyperthermia
2.  Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres 
The aim of this study was to prepare biodegradable sustained release magnetite microspheres sized between 1 to 2 μm. The microspheres with or without magnetic materials were prepared by a W/O/W double emulsion solvent evaporation technique using poly(lactide-co-glycolide) (PLGA) as the biodegradable matrix forming polymer. Effects of manufacturing and formulation variables on particle size were investigated with non-magnetic microspheres. Microsphere size could be controlled by modification of homogenization speed, PLGA concentration in the oil phase, oil phase volume, solvent composition, and polyvinyl alcohol (PVA) concentration in the outer water phase. Most influential were the agitation velocity and all parameters that influence the kinematic viscosity of oil and outer water phase, specifically the type and concentration of the oil phase. The magnetic component yielding homogeneous magnetic microspheres consisted of magnetite nanoparticles of 8 nm diameter stabilized with a polyethylene glycole/polyacrylic acid (PEG/PAA) coating and a saturation magnetization of 47.8 emu/g. Non-magnetic and magnetic microspheres had very similar size, morphology, and size distribution, as shown by scanning electron microscopy. The optimized conditions yielded microspheres with 13.7 weight% of magnetite and an average diameter of 1.37 μm. Such biodegradable magnetic microspheres seem appropriate for vascular administration followed by magnetic drug targeting.
doi:10.1186/1477-044X-5-2
PMCID: PMC1863415  PMID: 17407608
3.  Covalently modified magnetite nanoparticles with PEG: preparation and characterization as nano-adsorbent for removal of lead from wastewater 
Background
Lead is one of the hazardous materials which is associated with pollution and toxicity problems. This paper describes a novel approach for removal of lead from wastewater. Although naked magnetic nanoparticles have been applied for removal of different pollutants from wastewater, there was no research on employment of covalently PEG modified magnetic nanoparticles for such purpose.
Results
A magnetic nano-adsorbent was prepared by chemically modification of magnetite nanoparticles (MNPs) with polyethylene glycol (PEG) for removal of lead ions. The surface of MNPs was coated covalently with 3-aminopropyltriethoxysilane (APTES) and PEG. Modified MNPs (MNPs-APTES-PEG) were characterized by FT-IR, XRD, SEM, and particle size analysis. Compared to the oleic acid coated MNPs, MNPs-APTES-PEG exhibited significant higher uptake capability for Pb(II) ions. The effective parameters on the extent of adsorption (time, temperature, Pb(II) concentration, contact time and pH) were studied and optimized by response surface methodology. Maximum uptake of MNPs-APTES-PEG for Pb(II) was determined to be 81.39 ± 2.5%. The results showed that the kinetic data was best described by Pseudo-second order model as evidenced by the relatively high value of determination coefficient (R2 = 0.9998). Successful removal of Pb(II) from industrial wastewater was also accomplished by MNPs-APTES-PEG.
Conclusions
The results revealed high capability and excellent efficiency of developed nano-adsorbents in removal of lead contaminants from industrial wastewater.
doi:10.1186/2052-336X-12-103
PMCID: PMC4582999  PMID: 26413305
Nanotechnology; Nano-adsorbent; Magnetite; Wastewater; Response surface methodology
4.  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
5.  Intrinsically superparamagnetic Fe-hydroxyapatite nanoparticles positively influence osteoblast-like cell behaviour 
Background
Superparamagnetic nanoparticles (MNPs) have been progressively explored for their potential in biomedical applications and in particular as a contrast agent for diagnostic imaging, for magnetic drug delivery and more recently for tissue engineering applications. Considering the importance of having safe MNPs for such applications, and the essential role of iron in bone remodelling, this study developed and analysed novel biocompatible and bioreabsorbable superparamagnetic nanoparticles, that avoid the use of poorly tolerated magnetite based nanoparticles, for bone tissue engineering applications.
Results
MNPs were obtained by doping hydroxyapatite (HA) with Fe ions, by directly substituting Fe2+ and Fe3+ into the HA structure yielding superparamagnetic bioactive phase. In the current study, we have investigated the effects of increasing concentrations (2000 μg/ml; 1000 μg/ml; 500 μg/ml; 200 μg/ml) of FeHA MNPs in vitro using Saos-2 human osteoblast-like cells cultured for 1, 3 and 7 days with and without the exposure to a static magnetic field of 320 mT. Results demonstrated not only a comparable osteoblast viability and morphology, but increased in cell proliferation, when compared to a commercially available Ha nanoparticles, even with the highest dose used. Furthermore, FeHA MNPs exposure to the static magnetic field resulted in a significant increase in cell proliferation throughout the experimental period, and higher osteoblast activity.
In vivo preliminary results demonstrated good biocompatibility of FeHA superparamagnetic material four weeks after implantation into a critical size lesion of the rabbit condyle.
Conclusions
The results of the current study suggest that these novel FeHA MNPs may be particularly relevant for strategies of bone tissue regeneration and open new perspectives for the application of a static magnetic field in a clinical setting of bone replacement, either for diagnostic imaging or magnetic drug delivery.
doi:10.1186/1477-3155-10-32
PMCID: PMC3458931  PMID: 22828388
Nanoparticles; Superparamagnetism; Hydroxyapatite; Static magnetic field; Orthopaedic applications
6.  Magnetically driven plasmid DNA delivery with biodegradable polymeric nanoparticles 
The FASEB Journal  2007;21(10):2510-2519.
Targeting gene therapy remains a challenge. The use of magnetic force to achieve this was investigated in the present study. It was hypothesized that nanoparticles with both controllable particle size and magnetic properties would enable magnetically driven gene delivery. We investigated this hypothesis by creating a family of novel biodegradable polymeric superparamagnetic nanoparticle (MNP) formulations. Polylactide MNP were formulated using a modified emulsification-solvent evaporation methodology with both the incorporation of oleate-coated iron oxide and a polyethylenimine (PEI) oleate ion-pair surface modification for DNA binding. MNP size could be controlled by varying the proportion of the tetrahydrofuran cosolvent. Magnetically driven MNP-mediated gene transfer was studied using a green fluorescent protein reporter plasmid in cultured arterial smooth muscle cells and endothelial cells. MNP-DNA internalization and trafficking were examined by confocal microscopy. Cell growth inhibition after MNP-mediated adiponectin plasmid transfection was studied as an example of a therapeutic end point. MNP-DNA complexes protected DNA from degradation and efficiently transfected quiescent cells under both low and high serum conditions after a 15 min exposure to a magnetic field (500 G). There was negligible transfection with MNP in the absence of a magnetic field. Larger sized MNP (375 nm diameter) exhibited higher transfection rates compared with 185 nm- and 240 nm-sized MNP. Internalized larger sized MNP escaped lysosomal localization and released DNA in the perinuclear zone. Adiponectin plasmid DNA delivery using MNP resulted in a dose-dependent growth inhibition of cultured arterial smooth muscle cells. It is concluded that magnetically driven plasmid DNA delivery can be achieved using biodegradable MNP containing oleate-coated magnetite and surface modified with PEI oleate ion-pair complexes that enable DNA binding.
doi:10.1096/fj.06-8070com
PMCID: PMC3378388  PMID: 17403937
GFP plasmid; magnetic nanoparticles; ion-pair complex; polyethylenimine; adiponectin
7.  Design Maps for the Hyperthermic Treatment of Tumors with Superparamagnetic Nanoparticles 
PLoS ONE  2013;8(2):e57332.
A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase ΔT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m−1; and concentration cMNP varying from 0.02 to 3.5 mg ml−1. At high frequency field (∼30 MHz), non specific heating dominates and ΔT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the ΔT of the medium grows linearly with cMNP, whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H2. Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42°C) and thermal ablation (Ttissue >50°C) are derived in terms of cMNP, operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration – systemic versus intratumor injection – depending on the magnetic and biodistribution properties of the nanoparticles.
doi:10.1371/journal.pone.0057332
PMCID: PMC3581487  PMID: 23451208
8.  Synthesis, characterization, and antimicrobial activity of an ampicillin-conjugated magnetic nanoantibiotic for medical applications 
Because of their magnetic properties, magnetic nanoparticles (MNPs) have numerous diverse biomedical applications. In addition, because of their ability to penetrate bacteria and biofilms, nanoantimicrobial agents have become increasingly popular for the control of infectious diseases. Here, MNPs were prepared through an iron salt coprecipitation method in an alkaline medium, followed by a chitosan coating step (CS-coated MNPs); finally, the MNPs were loaded with ampicillin (amp) to form an amp-CS-MNP nanocomposite. Both the MNPs and amp-CS-MNPs were subsequently characterized and evaluated for their antibacterial activity. X-ray diffraction results showed that the MNPs and nanocomposites were composed of pure magnetite. Fourier transform infrared spectra and thermogravimetric data for the MNPs, CS-coated MNPs, and amp-CS-MNP nanocomposite were compared, which confirmed the CS coating on the MNPs and the amp-loaded nanocomposite. Magnetization curves showed that both the MNPs and the amp-CS-MNP nanocomposites were superparamagnetic, with saturation magnetizations at 80.1 and 26.6 emu g−1, respectively. Amp was loaded at 8.3%. Drug release was also studied, and the total release equilibrium for amp from the amp-CS-MNPs was 100% over 400 minutes. In addition, the antimicrobial activity of the amp-CS-MNP nanocomposite was determined using agar diffusion and growth inhibition assays against Gram-positive bacteria and Gram-negative bacteria, as well as Candida albicans. The minimum inhibitory concentration of the amp-CS-MNP nanocomposite was determined against bacteria including Mycobacterium tuberculosis. The synthesized nanocomposites exhibited antibacterial and antifungal properties, as well as antimycobacterial effects. Thus, this study introduces a novel β-lactam antibacterial-based nanocomposite that can decrease fungus activity on demand for numerous medical applications.
doi:10.2147/IJN.S61143
PMCID: PMC4134181  PMID: 25143729
iron oxide nanoparticles; chitosan; coating material; antibacterial activity; β-lactam; and nanoantibiotics
9.  Studying the effect of particle size and coating type on the blood kinetics of superparamagnetic iron oxide nanoparticles 
Purpose:
Magnetic resonance imaging (MRI), one of the most powerful imaging techniques available, usually requires the use of an on-demand designed contrast agent to fully exploit its potential. The blood kinetics of the contrast agent represent an important factor that needs to be considered depending on the objective of the medical examination. For particulate contrast agents, such as superparamagnetic iron oxide nanoparticles (SPIOs), the key parameters are particle size and characteristics of the coating material. In this study we analyzed the effect of these two properties independently and systematically on the magnetic behavior and blood half-life of SPIOs.
Methods:
Eleven different SPIOs were synthesized for this study. In the first set (a), seven carboxydextran (CDX)-coated SPIOs of different sizes (19–86 nm) were obtained by fractionating a broadly size-distributed CDX–SPIO. The second set (b) contained three SPIOs of identical size (50 nm) that were stabilized with different coating materials, polyacrylic acid (PAA), poly-ethylene glycol, and starch. Furthermore, small PAA–SPIOs (20 nm) were synthesized to gain a global insight into the effects of particle size vs coating characteristics. Saturation magnetization and proton relaxivity were determined to represent the magnetic and imaging properties. The blood half-life was analyzed in rats using MRI, time-domain nuclear magnetic resonance, and inductively coupled plasma optical emission spectrometry.
Results:
By changing the particle size without modifying any other parameters, the relaxivity r2 increased with increasing mean particle diameter. However, the blood half-life was shorter for larger particles. The effect of the coating material on magnetic properties was less pronounced, but it had a strong influence on blood kinetics depending on the ionic character of the coating material.
Conclusion:
In this report we systematically demonstrated that both particle size and coating material influence blood kinetics and magnetic properties of SPIO independently. These data provide key information for the selection of a contrast agent for a defined application and are additionally valuable for other nano areas, such as hyperthermia, drug delivery, and nanotoxicology.
doi:10.2147/IJN.S33120
PMCID: PMC3420593  PMID: 22927759
SPIO; relaxivity; blood half-life; MRI
10.  Gum Arabic-Coated Magnetic Nanoparticles for Potential Application in Simultaneous Magnetic Targeting and Tumor Imaging 
The AAPS Journal  2009;11(4):693.
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.
doi:10.1208/s12248-009-9151-y
PMCID: PMC2782085  PMID: 19842043
brain tumor; drug delivery; gum arabic; magnetic nanoparticle; magnetic targeting
11.  The impact of polymer coatings on magnetite nanoparticles performance as MRI contrast agents: a comparative study 
Background
Superparamagnetic iron oxide nanoparticles (SPIONs) are the most commonly used negative MRI contrast agent which affect the transverse (T2) relaxation time. The aim of the present study was to investigate the impact of various polymeric coatings on the performance of magnetite nanoparticles as MRI contrast agents.
Methods
Ferrofluids based on magnetite (Fe3O4) nanoparticles (SPIONs) were synthesized via chemical co-precipitation method and coated with different biocompatible polymer coatings including mPEG-PCL, chitosan and dextran.
Results
The bonding status of different polymers on the surface of the magnetite nanoparticles was confirmed by the Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA). The vibrating sample magnetometer (VSM) analysis confirmed the superparamagnetic behavior of all synthesized nanoparticles. The field–emission scanning electron microscopy (FE-SEM) indicated the formation of quasi-spherical nanostructures with the final average particle size of 12–55 nm depending on the type of polymer coating, and X-ray diffraction (XRD) determined inverse spinel structure of magnetite nanoparticles. The ferrofluids demonstrated sufficient colloidal stability in deionized water with the zeta potentials of −24.2, −16.9, +31.6 and −21 mV for the naked SPIONs, and for dextran, chitosan and mPEG-PCL coated SPIONs, respectively. Finally, the magnetic relaxivities of water based ferrofluids were measured on a 1.5T clinical MRI instrument. The r2/r1 value was calculated to be 17.21, 19.42 and 20.71 for the dextran, chitosan and mPEG-PCL coated SPIONs, respectively.
Conclusions
The findings demonstrated that the value of r2/r1 ratio of mPEG-PCL modified SPIONs is higher than that of some commercial contrast agents. Therefore, it can be considered as a promising candidate for T2 MRI contrast agent.
doi:10.1186/s40199-015-0124-7
PMCID: PMC4574187  PMID: 26381740
12.  The efficiency of magnetic hyperthermia and in vivo histocompatibility for human-like collagen protein-coated magnetic nanoparticles 
Magnetic hyperthermia is a promising technique for the minimally invasive elimination of solid tumors. In this study, uniform magnetite nanoparticles (MNPs) with different particle sizes were used as a model system to investigate the size and surface effects of human-like collagen protein-coated MNPs (HLC-MNPs) on specific absorption rate and biocompatibility. It was found that these HLC-MNPs possess rapid heating capacity upon alternating magnetic field exposure compared to that of MNPs without HLC coating, irrespective of the size of MNPs. The significant enhancement of specific absorption rate is favorable for larger sized nanoparticles. Such behavior is attributed to the reduced aggregation and increased stability of the HLC-MNPs. By coating HLC on the surface of certain sized MNPs, a significant increase in cell viability (up to 2.5-fold) can be achieved. After subcutaneous injection of HLC-MNPs into the back of Kunming mice, it was observed that the inflammatory reaction hardly occurred in the injection site. However, there was a significant presence of phagocytes and endocytosis after the injection of nonconjugated counterparts. The overall strategy to fabricate HLC-MNPs can serve as a general guideline to address the current challenges in clinical magnetic hyperthermia, improved biocompatibility, and enhanced heating characteristics through protein coating.
doi:10.2147/IJN.S101741
PMCID: PMC4809344  PMID: 27042065
Fe3O4 nanoparticles; human-like collagen protein; SAR value; biocompatibility
13.  Stability and magnetically induced heating behavior of lipid-coated Fe3O4 nanoparticles 
Nanoscale Research Letters  2013;8(1):426.
Magnetic nanoparticles that are currently explored for various biomedical applications exhibit a high propensity to minimize total surface energy through aggregation. This study introduces a unique, thermoresponsive nanocomposite design demonstrating substantial colloidal stability of superparamagnetic Fe3O4 nanoparticles (SPIONs) due to a surface-immobilized lipid layer. Lipid coating was accomplished in different buffer systems, pH 7.4, using an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG). Particle size and zeta potential were measured by dynamic laser light scattering. Heating behavior within an alternating magnetic field was compared between the commercial MFG-1000 magnetic field generator at 7 mT (1 MHz) and an experimental, laboratory-made magnetic hyperthermia system at 16.6 mT (13.7 MHz). The results revealed that product quality of lipid-coated SPIONs was significantly dependent on the colloidal stability of uncoated SPIONs during the coating process. Greatest stability was achieved at 0.02 mg/mL in citrate buffer (mean diameter = 80.0 ± 1.7 nm; zeta potential = -47.1 ± 2.6 mV). Surface immobilization of an equimolar DPPC/DPPG layer effectively reduced the impact of buffer components on particle aggregation. Most stable suspensions of lipid-coated nanoparticles were obtained at 0.02 mg/mL in citrate buffer (mean diameter = 179.3 ± 13.9 nm; zeta potential = -19.1 ± 2.3 mV). The configuration of the magnetic field generator significantly affected the heating properties of fabricated SPIONs. Heating rates of uncoated nanoparticles were substantially dependent on buffer composition but less influenced by particle concentration. In contrast, thermal behavior of lipid-coated nanoparticles within an alternating magnetic field was less influenced by suspension vehicle but dramatically more sensitive to particle concentration. These results underline the advantages of lipid-coated SPIONs on colloidal stability without compromising magnetically induced hyperthermia properties. Since phospholipids are biocompatible, these unique lipid-coated Fe3O4 nanoparticles offer exciting opportunities as thermoresponsive drug delivery carriers for targeted, stimulus-induced therapeutic interventions.
PACS
7550Mw; 7575Cd; 8185Qr
doi:10.1186/1556-276X-8-426
PMCID: PMC3853621  PMID: 24134544
SPION; Magnetic field generator; Hyperthermia; Phospholipid; Thermoresponsive; Colloid
14.  Impact of magnetic field parameters and iron oxide nanoparticle properties on heat generation for use in magnetic hyperthermia 
Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1 to 47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.
doi:10.1016/j.jmmm.2015.03.085
PMCID: PMC4422114  PMID: 25960599
Magnetic fluid hyperthermia; iron oxide nanoparticles; magnetic field strength; magnetic field frequency; specific absorption rate
15.  Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study 
Background:
Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents.
Methods:
Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents.
Results:
Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM−1 s−1), respectively.
Conclusion:
The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works.
PMCID: PMC4483316  PMID: 26140183
Magnetite Nanoparticles; MR imaging; Prostatic neoplasm
16.  Bleomycin Loaded Magnetite Nanoparticles Functionalized by Polyacrylic Acid as a New Antitumoral Drug Delivery System 
BioMed Research International  2013;2013:462589.
Objective. To prepare, characterize, and analyze the release behavior of bleomycin-loaded magnetite nanoparticles (BLM-MNPs) coated with polyacrylic acid (PAA) as a new drug delivery system that can be specifically distributed in the tumor site. Methods. BLM-MNPs coated with PAA were prepared using a solvothermal approach. The particles were characterized using scanning electron microscope (SEM), vibrating sample magnetometer (VSM), and Fourier transform infrared spectroscopy (FTIR). The loading and release behaviors of BLM-MNPs were examined by a mathematical formula and in vitro release profile at pH 7.5. Results. The sphere Fe3O4 nanoparticles with the size of approximately 30 nm exhibit a saturation magnetization of 87 emu/g. The noncoordinated carboxylate groups of PAA confer on the good dispersibility in the aqueous solution and lead to a good loading efficiency of BLM reaching 50% or higher. Approximately 98% of immobilized BLM could be released within 24 h, of which 22.4% was released in the first hour and then the remaining was released slowly and quantitatively in the next 23 hours. Conclusion. BLM-MNPs were prepared and characterized successfully. The particles show high saturation magnetization, high drug loading capacity, and favorable release property, which could contribute to the specific delivery and controllable release of BLM, and the BLM-MNPs could be a potential candidate for the development of treating solid tumors.
doi:10.1155/2013/462589
PMCID: PMC3747614  PMID: 23998124
17.  Water dispersion of magnetic nanoparticles with selective Biofunctionality for enhanced plasmonic biosensing 
Talanta  2016;151:23-29.
Magnetic nanoparticles (MNPs) are widely used in biosensing, bioimaging, and drug delivery. However, high quality superparamagnetic nanoparticles with uniform size were usually synthesized by thermal decomposition using organic solvents. To be suitable for biomedical applications, a facile and efficient water dispersion of iron oxide MNPs from solvent using an innovative agent, sodium oleate (NaOL) was described. The monodispersed MNPs (4 and 15 nm respectively) after transfer was biocompatible and stable at a broad temperature range (4–50°C) over months. More importantly, the NaOL coating allows for surface modification with selective functionality, rendering the aqueous MNPs highly customizable for biofunctionalization. Little effect on the superparamagnetism was observed after the water dispersion. To further evaluate its practical application in biosensing, custom MNPs were prepared for specific cardiac troponin I (cTnI) detection for myocardial infarction diagnosis. Specifically, gold nanorod (GNR) biochip was probed by the MNP-captured cTnI target analyte at varying concentrations. The signal transduction of the GNR sensor is based on the localized surface plasmon resonance (LSPR). The application of the MNPs resulted in a significant enhancement of the plasmonic response of the GNRs. As such, the MNP-mediated LSPR biosenisng showed a three times lower sensitivity as compared to the direct cTnI binding without functional MNPs. Computer simulation further elucidated that the enhancement was distance dependent between the MNP and the surface of the nanorod, which corroborated with experimental results.
doi:10.1016/j.talanta.2016.01.007
PMCID: PMC4856218  PMID: 26946006
Magnetic nanoparticle; Phase transfer; Gold nanorod biochip; Surface plasmon resonance; Cardiac troponin I; Heart attack diagnosis
18.  Size-regulated group separation of CoFe2O4 nanoparticles using centrifuge and their magnetic resonance contrast properties 
Nanoscale Research Letters  2013;8(1):376.
Magnetic nanoparticle (MNP)-based magnetic resonance imaging (MRI) contrast agents (CAs) have been the subject of extensive research over recent decades. The particle size of MNPs varies widely and is known to influence their physicochemical and pharmacokinetic properties. There are two commonly used methods for synthesizing MNPs, organometallic and aqueous solution coprecipitation. The former has the advantage of being able to control the particle size more effectively; however, the resulting particles require a hydrophilic coating in order to be rendered water soluble. The MNPs produced using the latter method are intrinsically water soluble, but they have a relatively wide particle size distribution. Size-controlled water-soluble MNPs have great potential as MRI CAs and in cell sorting and labeling applications. In the present study, we synthesized CoFe2O4 MNPs using an aqueous solution coprecipitation method. The MNPs were subsequently separated into four groups depending on size, by the use of centrifugation at different speeds. The crystal shapes and size distributions of the particles in the four groups were measured and confirmed by transmission electron microscopy and dynamic light scattering. Using X-ray diffraction analysis, the MNPs were found to have an inverse spinel structure. Four MNP groups with well-selected semi-Gaussian-like diameter distributions were obtained, with measured T2 relaxivities (r2) at 4.7 T and room temperature in the range of 60 to 300 mM−1s−1, depending on the particle size. This size regulation method has great promise for applications that require homogeneous-sized MNPs made by an aqueous solution coprecipitation method. Any group of the CoFe2O4 MNPs could be used as initial base cores of MRI T2 CAs, with almost unique T2 relaxivity owing to size regulation. The methodology reported here opens up many possibilities for biosensing applications and disease diagnosis.
PACS
75.75.Fk, 78.67.Bf, 61.46.Df
doi:10.1186/1556-276X-8-376
PMCID: PMC3844441  PMID: 24004536
Magnetic nanoparticles; Magnetic resonance imaging; Relaxivity; Particle size regulation
19.  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
20.  Conjugation Magnetic PAEEP-PLLA Nanoparticles with Lactoferrin as a Specific Targeting MRI Contrast Agent for Detection of Brain Glioma in Rats 
The diagnosis of malignant brain gliomas is largely based on magnetic resonance imaging (MRI) with contrast agents. In recent years, nano-sized contrast agents have been developed for improved MRI diagnosis. In this study, oleylamine-coated Fe3O4 magnetic nanoparticles (OAM-MNPs) were synthesized with thermal decomposition method and encapsulated in novel amphiphilic poly(aminoethyl ethylene phosphate)/poly(L-lactide) (PAEEP-PLLA) copolymer nanoparticles. The OAM-MNP-loaded PAEEP-PLLA nanoparticles (M-PAEEP-PLLA-NPs) were further conjugated with lactoferrin (Lf) for glioma tumor targeting. The Lf-conjugated M-PAEEP-PLLA-NPs (Lf-M-PAEEP-PLLA-NPs) were characterized by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The average size of OAM-MNPs, M-PAEEP-PLLA-NPs, and Lf-M-PAEEP-PLLA-NPs were 8.6 ± 0.3, 165.7 ± 0.6, and 218.2 ± 0.4 nm, with polydispersity index (PDI) of 0.185 ± 0.023, 0.192 ± 0.021, and 0.224 ± 0.036, respectively. TEM imaging showed that OAM-MNPs were monodisperse and encapsulated in Lf-M-PAEEP-PLLA-NPs. TGA analysis showed that the content of iron oxide nanoparticles was 92.8 % in OAM-MNPs and 45.2 % in Lf-M-PAEEP-PLLA-NPs. VSM results indicated that both OAM-MNPs and Lf-M-PAEEP-PLLA-NPs were superparamagnetic, and the saturated magnetic intensity were 77.1 and 74.8 emu/g Fe. Lf-M-PAEEP-PLLA-NPs exhibited good biocompatibility in cytotoxicity assay. The high cellular uptake of Lf-M-PAEEP-PLLA-NPs in C6 cells indicated that Lf provided effective targeting for the brain tumor cells. The T2 relaxation rate (r2) of M-PAEEP-PLLA-NPs and Lf-M-PAEEP-PLLA-NPs were calculated to be 167.2 and 151.3 mM−1 s−1. In MRI on Wistar rat-bearing glioma tumor, significant contrast enhancement could clearly appear at 4 h after injection and last 48 h. Prussian blue staining of the section clearly showed the retention of Lf-M-PAEEP-PLLA-NPs in tumor tissues. The results from the in vitro and in vivo MRI indicated that Lf-M-PAEEP-PLLA-NPs possessed strong, long-lasting, tumor targeting, and enhanced tumor MRI contrast ability. Lf-M-PAEEP-PLLA-NPs represent a promising nano-sized MRI contrast agent for brain glioma targeting MRI.
doi:10.1186/s11671-016-1421-x
PMCID: PMC4848283  PMID: 27119155
Poly(aminoethyl ethylene phosphate)/poly (L-lactide) copolymer; Oleylamine-coated Fe3O4 nanoparticles; Lactoferrin; Superparamagnetic; MRI contrast agent; Brain glioma targeting
21.  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
22.  Size dependent heat generation of magnetite nanoparticles under AC magnetic field for cancer therapy 
Background
We have developed magnetic cationic liposomes (MCLs) that contained magnetic nanoparticles as heating mediator for applying them to local hyperthermia. The heating performance of the MCLs is significantly affected by the property of the incorporated magnetite nanoparticles. We estimated heating capacity of magnetite nanoparticles by measuring its specific absorption rate (SAR) against irradiation of the alternating magnetic field (AMF).
Method
Magnetite nanoparticles which have various specific-surface-area (SSA) are dispersed in the sample tubes, subjected to various AMF and studied SAR.
Result
Heat generation of magnetite particles under variable AMF conditions was summarized by the SSA. There were two maximum SAR values locally between 12 m2/g to 190 m2/g of the SSA in all ranges of applied AMF frequency and those values increased followed by the intensity of AMF power. One of the maximum values was observed at approximately 90 m2/g of the SSA particles and the other was observed at approximately 120 m2/g of the SSA particles. A boundary value of the SAR for heat generation was observed around 110 m2/g of SSA particles and the effects of the AMF power were different on both hand. Smaller SSA particles showed strong correlation of the SAR value to the intensity of the AMF power though larger SSA particles showed weaker correlation.
Conclusion
Those results suggest that two maximum SAR value stand for the heating mechanism of magnetite nanoparticles represented by hysteresis loss and relaxation loss.
doi:10.1186/1477-044X-6-4
PMCID: PMC2579422  PMID: 18928573
23.  Novel kojic acid-polymer-based magnetic nanocomposites for medical applications 
Iron oxide magnetic nanoparticles (MNPs) were synthesized by the coprecipitation of iron salts in sodium hydroxide followed by coating separately with chitosan (CS) and polyethylene glycol (PEG) to form CS-MNPs and PEG-MNPs nanoparticles, respectively. They were then loaded with kojic acid (KA), a pharmacologically bioactive natural compound, to form KA-CS-MNPs and KA-PEG-MNPs nanocomposites, respectively. The MNPs and their nanocomposites were characterized using powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, vibrating sample magnetometry, and scanning electron microscopy. The powder X-ray diffraction data suggest that all formulations consisted of highly crystalline, pure magnetite Fe3O4. The Fourier transform infrared spectroscopy and thermogravimetric analysis confirmed the presence of both polymers and KA in the nanocomposites. Magnetization curves showed that both nanocomposites (KA-CS-MNPs and KA-PEG-MNPs) were superparamagnetic with saturation magnetizations of 8.1 emu/g and 26.4 emu/g, respectively. The KA drug loading was estimated using ultraviolet–visible spectroscopy, which gave a loading of 12.2% and 8.3% for the KA-CS-MNPs and KA-PEG-MNPs nanocomposites, respectively. The release profile of the KA from the nanocomposites followed a pseudo second-order kinetic model. The agar diffusion test was performed to evaluate the antimicrobial activity for both KA-CS-MNPs and KA-PEG-MNPs nanocomposites against a number of microorganisms using two Gram-positive (methicillin-resistant Staphylococcus aureus and Bacillus subtilis) and one Gram-negative (Salmonella enterica) species, and showed some antibacterial activity, which could be enhanced in future studies by optimizing drug loading. This study provided evidence for the promise for the further investigation of the possible beneficial biological activities of KA and both KA-CS-MNPs and KA-PEG-MNPs nanocomposites in nanopharmaceutical applications.
doi:10.2147/IJN.S53847
PMCID: PMC3890966  PMID: 24453486
chitosan; polyethylene glycol; magnetic nanoparticle; kojic acid; controlled release; biological activity
24.  Tangential Flow Ultrafiltration Allows Purification and Concentration of Lauric Acid-/Albumin-Coated Particles for Improved Magnetic Treatment 
Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEONLA-BSA, which were synthesized using excess albumin. For optimization of magnetic treatment applications, SPION suspensions need to be purified of excess surfactant and concentrated. Conventional methods for the purification and concentration of such ferrofluids often involve high shear stress and low purification rates for macromolecules, like albumin. In this work, removal of albumin by low shear stress tangential ultrafiltration and its influence on SEONLA-BSA particles was studied. Hydrodynamic size, surface properties and, consequently, colloidal stability of the nanoparticles remained unchanged by filtration or concentration up to four-fold (v/v). Thereby, the saturation magnetization of the suspension can be increased from 446.5 A/m up to 1667.9 A/m. In vitro analysis revealed that cellular uptake of SEONLA-BSA changed only marginally. The specific absorption rate (SAR) was not greatly affected by concentration. In contrast, the maximum temperature Tmax in magnetic hyperthermia is greatly enhanced from 44.4 °C up to 64.9 °C by the concentration of the particles up to 16.9 mg/mL total iron. Taken together, tangential ultrafiltration is feasible for purifying and concentrating complex hybrid coated SPION suspensions without negatively influencing specific particle characteristics. This enhances their potential for magnetic treatment.
doi:10.3390/ijms160819291
PMCID: PMC4581297  PMID: 26287178
hyperthermia; nanoparticle concentration; tangential ultrafiltration; nanoparticle purification; specific absorption rate (SAR); superparamagnetic iron oxide nanoparticles (SPIONs)
25.  Dual-responsive polymer-coated iron oxide nanoparticles for drug delivery and imaging applications 
We reported the synthesis and characterization of dual-responsive poly(N-isopropylacrylamide-acrylamide-chitosan) (PAC)-coated magnetic nanoparticles (MNPs) for controlled and targeted drug delivery and imaging applications. The PAC-MNPs size was about 150 nm with 70% iron mass content and excellent superparamagnetic properties. PAC-MNPs loaded with anti-cancer drug doxorubicin showed dual-responsive drug release characteristics with the maximum release of drugs at 40 °C (~78%) than at 37 °C (~33%) and at pH of 6 (~55%) than at pH of 7.4 (~28%) after 21 days. Further, the conjugation of prostate cancer-specific R11 peptides increased the uptake of PAC-MNPs by prostate cancer PC3 cells. The dose-dependent cellular uptake of the nanoparticles was also significantly increased with the presence of 1.3 T magnetic field. The nanoparticles demonstrated cytocompatibility up to concentrations of 500 μg/ ml when incubated over a period of 24 h with human dermal fibroblasts and normal prostate epithelial cells. Finally, pharmacokinetic studies indicated that doxorubicin-loaded PAC-MNPs caused significant prostate cancer cell death at 40 °C than at 37 °C, thereby confirming the temperature-dependent drug release kinetics and in vitro therapeutic efficacy. Future evaluation of in vivo therapeutic efficacy of targeted image-guided cancer therapy using R11-PAC-MNPs will reinforce a significant impact of the multifunctional PAC-MNPs on the future drug delivery systems.
doi:10.1016/j.ijpharm.2014.03.016
PMCID: PMC4642438  PMID: 24607216
Poly(N-isopropylacrylamide); Chitosan; Iron oxide magnetic nanoparticles; Prostate cancer; Dual-responsiveness

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