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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.  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
4.  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
5.  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
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.  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
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.  Gum Arabic-Coated Magnetic Nanoparticles for Potential Application in Simultaneous Magnetic Targeting and Tumor Imaging 
The AAPS Journal  2009;11(4):693-699.
Magnetic iron oxide nanoparticles (MNP) coated with gum arabic (GA), a biocompatible phytochemical glycoprotein widely used in the food industry, were successfully synthesized and characterized. GA-coated MNP (GA-MNP) displayed a narrow hydrodynamic particle size distribution averaging about 100 nm; a GA content of 15.6% by dry weight; a saturation magnetization of 93.1 emu/g Fe; and a superparamagnetic behavior essential for most magnetic-mediated applications. The GA coating offers two major benefits: it both enhances colloidal stability and provides reactive functional groups suitable for coupling of bioactive compounds. In vitro results showed that GA-MNP possessed a superior stability upon storage in aqueous media when compared to commercial MNP products currently used in magnetic resonance imaging (MRI). In addition, significant cellular uptake of GA-MNP was evaluated in 9L glioma cells by electron spin resonance (ESR) spectroscopy, fluorescence microscopy, and MRI analyses. Based on these findings, it was hypothesized that GA-MNP might be utilized as a MRI-visible drug carrier in achieving both magnetic tumor targeting and intracellular drug delivery. Indeed, preliminary in vivo investigations validate this clinical potential. MRI visually confirmed the accumulation of GA-MNP at the tumor site following intravenous administration to rats harboring 9L glioma tumors under the application of an external magnetic field. ESR spectroscopy quantitatively revealed a 12-fold increase in GA-MNP accumulation in excised tumors when compared to contralateral normal brain. Overall, the results presented show promise that GA-MNP could potentially be employed to achieve simultaneous tumor imaging and targeted intra-tumoral drug delivery.
doi:10.1208/s12248-009-9151-y
PMCID: PMC2782085  PMID: 19842043
brain tumor; drug delivery; gum arabic; magnetic nanoparticle; magnetic targeting
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  The Assembly State between Magnetic Nanosensors and their Targets Orchestrates their Magnetic Relaxation Response 
The target-induced clustering of magnetic nanoparticles is typically used for the identification of clinically relevant targets and events. A decrease in the water proton transverse NMR relaxation time, or T2, is observed upon clustering, allowing the sensitive and accurate detection of target molecules. We have discovered a new mechanistically unique nanoparticle-target interaction resulting in T2 increase, and demonstrate herein that this increase, and its associated r2 relaxivity decrease, is also observed upon the interaction of the nanoparticles with ligands or molecular entities. Small molecules, proteins, and a 15-bp nucleic acid sequence were chemically conjugated to polyacrylic-acid-coated iron oxide nanoparticles, and all decreased the original nanoparticle r2 value. Further experiments established that the r2 decrease was inversely proportional to the number of ligands bound to the nanoparticle and the molecular weight of the bound ligand. Additional experiments revealed that the T2-increasing mechanism was kinetically faster than the conventional clustering mechanism. Most importantly, under conditions that result in T2 increases, as little as 5.3 fmol of Bacillus anthracis plasmid DNA (pX01 and pX02), 8 pmol of the cholera toxin B subunit (Ctb), and even a few cancer cells in blood were detected. Transition from the binding to the clustering mechanism was observed in the carbohydrate-, Ctb- and DNA-sensing systems, simply by increasing the target concentration significantly above the nanoparticle concentration, or using Ctb in its pentameric form as opposed to its monomer. Collectively, these results demonstrate that the molecular architectures resulting from the interaction between magnetic nanosensors and their targets directly govern water proton NMR signal relaxation. We attribute the observed T2 increases to the bound target molecules partially obstructing the diffusion of solvent water molecules through the iron oxide nanoparticles’ outer relaxation spheres of the superparamagnetic nanoparticles. Finally, we anticipate that this novel interaction can be incorporated into new clinical and field detection applications, due to its faster kinetics relative to the conventional nanoparticle-clustering assays.
doi:10.1021/ja1109584
PMCID: PMC3053437  PMID: 21341659
18.  Conquering the Dark Side: Colloidal Iron Oxide Nanoparticles 
ACS nano  2009;3(12):3917-3926.
Nanomedicine approaches to atherosclerotic disease will have significant impact on the practice and outcomes of cardiovascular medicine. Iron oxide nanoparticles have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties, which typically result in negative contrast effects that can only be imaged 24 or more hours after systemic administration due to persistent blood pool interference. Although recent advances involving MR pulse sequences have converted these dark contrast voxels into bright ones, the marked delays in imaging from persistent magnetic background interference and prominent dipole blooming effects of the magnetic susceptibility remain barriers to overcome. We report a T1-weighted (T1w) theranostic colloidal iron oxide nanoparticle platform, CION, which is achieved by entrapping oleate-coated magnetite particles within a cross-linked phospholipid nanoemulsion. Contrary to expectations, this formulation decreased T2 effects thus allowing positive T1w contrast detection down to low nanomolar concentrations. CION, a vascular constrained nanoplatform administered in vivo permitted T1w molecular imaging 1 hour after treatment without blood pool interference, although some T2 shortening effects on blood, induced by the superparamagnetic particles persisted. Moreover, CION was shown to encapsulate antiangiogenic drugs, like fumagillin, and retained them under prolonged dissolution, suggesting significant theranostic functionality. Overall, CION is a platform technology, developed with generally recognized as safe components, that overcomes the temporal and spatial imaging challenges associated with current iron oxide nanoparticle T2 imaging agents, and which has theranostic potential in vascular diseases for detecting unstable ruptured plaque or treating atherosclerotic angiogenesis.
doi:10.1021/nn900819y
PMCID: PMC2797561  PMID: 19908850
iron oxide; molecular imaging; drug delivery; angiogenesis; ruptured plaque; MRI
19.  Magnetic Nanoclusters with Hydrophilic Spacing for Dual Drug Delivery and Sensitive Magnetic Resonance Imaging 
Magnetic Block Ionomer Clusters (MBIClusters) with hydrophilic ionic cores and nonionic coronas have been prepared that have ultrahigh transverse NMR relaxivities together with capacities for incorporating high concentrations of polar antibiotic payloads. Magnetite-polymer nanoparticles were assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide-b-acrylate) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. The PEO blocks extended into aqueous media to keep the nanoparticles dispersed. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxide in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. The intensity average spacing between the magnetite nanoparticles within the clusters was estimated to be ~50 nm. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2’s) that increased from 190 to 604 s−1 mM Fe−1 measured at 1.4 T and 37 °C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are sensitive contrast agents.
doi:10.1039/C2TB00275B
PMCID: PMC4199085  PMID: 25328679
magnetite; block ionomer; relaxivity; contrast agent; MRI
20.  Manganese ferrite-based nanoparticles induce ex vivo, but not in vivo, cardiovascular effects 
Magnetic nanoparticles (MNPs) have been used for various biomedical applications. Importantly, manganese ferrite-based nanoparticles have useful magnetic resonance imaging characteristics and potential for hyperthermia treatment, but their effects in the cardiovascular system are poorly reported. Thus, the objectives of this study were to determine the cardiovascular effects of three different types of manganese ferrite-based magnetic nanoparticles: citrate-coated (CiMNPs); tripolyphosphate-coated (PhMNPs); and bare magnetic nanoparticles (BaMNPs). The samples were characterized by vibrating sample magnetometer, X-ray diffraction, dynamic light scattering, and transmission electron microscopy. The direct effects of the MNPs on cardiac contractility were evaluated in isolated perfused rat hearts. The CiMNPs, but not PhMNPs and BaMNPs, induced a transient decrease in the left ventricular end-systolic pressure. The PhMNPs and BaMNPs, but not CiMNPs, induced an increase in left ventricular end-diastolic pressure, which resulted in a decrease in a left ventricular end developed pressure. Indeed, PhMNPs and BaMNPs also caused a decrease in the maximal rate of left ventricular pressure rise (+dP/dt) and maximal rate of left ventricular pressure decline (−dP/dt). The three MNPs studied induced an increase in the perfusion pressure of isolated hearts. BaMNPs, but not PhMNPs or CiMNPs, induced a slight vasorelaxant effect in the isolated aortic rings. None of the MNPs were able to change heart rate or arterial blood pressure in conscious rats. In summary, although the MNPs were able to induce effects ex vivo, no significant changes were observed in vivo. Thus, given the proper dosages, these MNPs should be considered for possible therapeutic applications.
doi:10.2147/IJN.S64254
PMCID: PMC4099104  PMID: 25031535
cardiac function; isolated heart; magnetic fluids; magnetic nanoparticles; nanomedicine
21.  Controllable In-Situ Synthesis of Magnetite Coated Silica-Core Water-Dispersible Hybrid Nanomaterials 
Magnetite nanoparticle coated silica (Fe3O4@SiO2) hybrid nanomaterials hold an important position in the fields of cell imaging and drug delivery. Here we report a large scale synthetic procedure that allows attachment of magnetite nanoparticles onto a silica surface in-situ. Many different silica nanomaterials such as Stöber silica nanospheres, mesoporous silica nanoparticles, and hollow silica nanotube have been coated with a high density layer of water-dispersible magnetite nanoparticles. The size and attachment efficiency of the magnetite nanoparticle can be well tuned by adjusting the precursor concentration and reflux time. The functionalization of Fe3O4@SiO2 nanoparticles with dye molecules and biocompatible polymers impart optical imaging modality and good colloidal stability in either buffer solution or serum. The functionalized materials also exhibited strong potential as negative contrast agents in T2 weighted magnetic resonance imaging.
doi:10.1021/la4022867
PMCID: PMC3905686  PMID: 23889037
magnetite coated silica; in-situ attachment; water dispersible; cell imaging
22.  Magnetorelaxometry Assisting Biomedical Applications of Magnetic Nanoparticles 
Pharmaceutical Research  2011;29(5):1189-1202.
Due to their biocompatibility and small size, iron oxide magnetic nanoparticles (MNP) can be guided to virtually every biological environment. MNP are susceptible to external magnetic fields and can thus be used for transport of drugs and genes, for heat generation in magnetic hyperthermia or for contrast enhancement in magnetic resonance imaging of biological tissue. At the same time, their magnetic properties allow one to develop sensitive and specific measurement methods to non-invasively detect MNP, to quantify MNP distribution in tissue and to determine their binding state. In this article, we review the application of magnetorelaxometry (MRX) for MNP detection. The underlying physical properties of MNP responsible for the generation of the MRX signal with its characteristic parameters of relaxation amplitude and relaxation time are described. Existing single and multi-channel MRX devices are reviewed. Finally, we thoroughly describe some applications of MRX to cellular MNP quantification, MNP organ distribution and MNP-based binding assays. Providing specific MNP signals, a detection limit down to a few nanogram MNP, in-vivo capability in conscious animals and measurement times of a few seconds, MRX is a valuable tool to improve the application of MNP for diagnostic and therapeutic purposes.
doi:10.1007/s11095-011-0630-3
PMCID: PMC3332344  PMID: 22161287
magnetic binding assay; magnetic drug targeting; magnetic nanoparticles; magnetofection; nanoparticle biodistribution
23.  Size-Tunable Synthesis of Stable Superparamagnetic Iron Oxide Nanoparticles for Potential Biomedical Applications 
Dextran-coated superparamagnetic nanoparticles (MNPs) have widespread biomedical applications. The superparamagnetic behavior, specifically regulated size, and smooth morphology are crucial requirements for essentially all of these applications. Presented herein is an innovative double-coating strategy that would allow for a size-controlled synthesis of MNPs. Small monocrystalline iron oxide nanoparticles (MIONs) were first synthesized, which served as the source of superparamagnetic properties. These MIONs were then treated in an acetate buffer containing biocompatible dextran polymer. Under such an environment, the colloidal MIONs would be quickly agglomerated by the acetate ions, and the formed coalescent body of MION would then be stabilized simultaneously by coating with dextran. By regulating the MION or dextran concentration as well as the thermal incubation time, the sizes of these first formed nanoparticles (termed 1st-NPs) could be readily controlled. A second dextran coating step was further applied to smoothen the 1st-NPs in attaining a final product (termed 2nd-NPs). The 2nd-NPs exhibited robustly storage stability due to the additional coating shell. Results successfully confirmed the plausibility of this approach, as these MNPs displayed not only a smooth outline and a narrow size distribution, but also the essential superparamagnetic behavior and a significantly prolonged stability upon storage.
doi:10.1002/jbm.a.32489
PMCID: PMC2818136  PMID: 19402138
superparamagnetic nanoparticle; size regulation; stable storage; double coating
24.  Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content 
Purpose
Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations.
Materials and methods
Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity.
Results
No cytotoxicity was observed at twice the target intracellular iron concentration (~100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties.
Conclusions
This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.
doi:10.3109/02656736.2014.913321
PMCID: PMC4327906  PMID: 24773041
Magnetic iron oxide nanoparticles; magnetic nanoparticle hyperthermia; magnetic resonance imaging; cancer
25.  Preparation, characterization, in vivo and in vitro studies of arsenic trioxide Mg-Fe ferrite magnetic nanoparticles 
Acta Pharmacologica Sinica  2009;30(12):1688-1693.
Aim:
MgFe2O4 magnetic nanoparticle composed of As2O3 (As2O3-MNPs) were prepared and their in vitro and in vivo characteristics were studied.
Methods:
The solvent-displacement method was applied for preparation of the nanoparticle using Poly-D,L-lactic-co-glycolic acid(PLGA). The characteristics studies of the products included magnetic response, morphology (transmission electron microscopy and scanning electron microscopy), entrapment efficiency, drug loading, particle sizes, zeta potential, in vitro drug release and tissue magnetic targeting. Nanoparticle cytotoxicity to Saos-2 cells was investigated using the MTT assay. To guide the external magnetic field in the liver, the concentration of As2O3 in the liver and kidney was measured using an atomic fluorescence spectrometer after injecting As2O3-MNPs into the caudal veins of mice.
Results:
The As2O3-MNPs were approximately spherical. The average diameter, drug loading, entrapment efficiency and zeta potential of As2O3-MNPs were 109.9 nm, 10.08%, 82.16%, and −14.33 mV, respectively. The specific saturation magnetism was 8.65 emu/g. In vivo, the concentration of As2O3 in the liver was significantly higher than that in the non-magnetic group. While the concentration of As2O3 in the kidney was lower than that in the non-magnetic group. The Cmax in liver tissue in the magnetic group was 30.65 μg/g, which was 4.17 times the drug concentration in the same group in kidney tissue (7.35 μg/g) and 2.88 times the concentration of drug (10.66 μg/g) in the liver tissue of the non-magnetic group.
Conclusion:
The PLGA polymer-loaded magnetic nanoparticle composed of arsenic trioxide can be magnetically targeted well and applied in biomedicine.
doi:10.1038/aps.2009.158
PMCID: PMC4007504  PMID: 19960013
As2O3; PLGA; magnetic nanoparticle; Mg-Fe ferrite; targeting

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