Pseudo single domain NiZn-γFe2O3colloidal superparamagnetic nanoparticles for MRI-guided hyperthermia application.

Magnetic resonance imaging (MRI)-guided magnetic nanofluid hyperthermia (MNFH) is highly desirable in cancer treatment because it can allow for diagnosis, therapeutics, and prognosis simultaneously. However, the application of currently developed iron-oxide based superparamagnetic nanoparticles (IOSPNPs) for an MRI-guided MNFH agent is technically limited by the low AC heat induction power at the physiologically tolerable range of AC magnetic field (HAC,safe), and the low transverser2-relaxivity responsible for the insufficient heating of cancers, and the low resolution of contrast imaging, respectively. Here, pseudo single domain colloidal NixZn1-x-γFe2O3(x = 0.6) superparamagnetic nanoparticle (NiZn-γFe2O3PSD-SPNP) physically and theoretically designed at theHAC,safe, specifically by the applied frequency, is proposed for a highly enhanced MRI-guided MNFH agent application. The NiZn-γFe2O3PSD-SPNP showed the superparamagnetic characteristics, significantly enhanced AC heat induction performance (ILP = 6.3 nHm2kg-1), highly improved saturation magnetization (Ms= 97 emu g-1Fe, 3.55 × 105A m-1) andr2-relaxivity (r2 = 396 mM-1s-1) that are desirable for highly efficient MRI-guided MNFH agent applications. According to the analyzed results, the remarkably enhanced effective relaxation time constant and its dependent out-of-phase magnetic susceptibility, as well as the DC/AC magnetic softness optimized by the PSD-SPNP at theHAC,safewere revealed as the main physical reason for the significance. All the fundamentalin vitroandin vivoexperimental results demonstrated that the physically designed NiZn-γFe2O3PSD-SPNP is bio-technically feasible for a highly efficient MRI-guided MNFH agent for future cancer nanomedicine.

The role of Co2+cation addition in enhancing the AC heat induction power of (CoxMn1-x)Fe2O4superparamagnetic nanoparticles.

The physical role of magnetically semi-hard Co2+cation addition in enhancing the AC heat induction temperature (TAC) or specific loss power (SLP) of solid (CoxMn1-x)Fe2O4superparamagnetic iron oxide nanoparticles (SPIONPs) was systematically investigated at the biologically safe and physiologically tolerable range ofHAC(HAC,safe= 1.12 × 109A m-1s-1,fappl= 100 kHz,Happl= 140 Oe (11.2 A m-1)) to demonstrate which physical parameter would be the most critical and dominant in enhancing theTAC(SLP) of SPIONPs. According to the experimentally and theoretically analyzed results, it was clearly demonstrated that the enhancement of magnetic anisotropy (Ku)-dependent AC magnetic softness including the Néel relaxation time constantτN(≈τeff, effective relaxation time constant), and its dependent out-of-phase magnetic susceptibilityχ″primarily caused by the Co2+cation addition is the most dominant parameter to enhance theTAC(SLP). This clarified result strongly suggests that the development of new design and synthesis methods enabling to significantly enhance theKuby improving the crystalline anisotropy, shape anisotropy, stress (magnetoelastic) anisotropy, thermally-induced anisotropy, and exchange anisotropy is the most critical to enhance theTAC(SLP) of SPIONPs at theHAC,safe(particularly at the lowerfappl< 120 kHz) for clinically safe magnetic nanoparticle hyperthermia.

External magnetic field dependent shift of superparamagnetic blocking temperature due to core/surface disordered spin interactions.

Although the blocking temperature of superparamagnetic nanoparticles (SPNPs) is crucial for various spintronics and biomedical applications, the precise determination of the blocking temperature is still not clear. Here, we present 'intrinsic' and 'extrinsic' characteristics of the blocking temperature in SPNP systems. In zero-field-cooled/field-cooled (ZFC-FC) curves, there was no shift of 'intrinsic blocking temperature' at different applied external (excitation) magnetic fields. However, 'extrinsic blocking temperature' shift is clearly dependent on the external (excitation) magnetic field. According to our newly proposed physical model, the 'intermediate spin layer' located between the core and surface disordered spin layers is primarily responsible for the physical nature of the shift of extrinsic blocking temperature. Our new findings offer possibilities for characterizing the thermally induced physical properties of SPNPs. Furthermore, these findings provide a new empirical approach to indirectly estimate the qualitative degree of the disordered surface spin status in SPNPs.

Physical contribution of Néel and Brown relaxation to interpreting intracellular hyperthermia characteristics using superparamagnetic nanofluids.

In this work, the AC magnetically-induced heating characteristics of various viscous nanofluids with either soft ferrite (Fe3O4) or hard ferrite (CoFe2O4) superparamagnetic nanoparticles (SPNPs) were investigated to empirically and physically interpret the contribution of "Néel relaxation loss power, P(Néel relaxation loss)," or "Brown relaxation loss power, P(Brown relaxation loss)," to the total AC heat generation of intracellular hyperthermia or in-vivo hyperthermia. It was found that the contribution of P(Brown relaxation loss) to the total AC heating power, P(totaI), and the specific loss power (SLP) was severely affected by the surrounding environment (or in-vivo environment) while the contribution of P(Néel relaxation loss) to the P(total) was independent of the variation of surrounding environment. Furthermore, all the theoretical and experimental results strongly suggested that highly efficacious intracellular hyperthermia (or in-vivo hyperthermia) modality can be achieved by enhancing the P(Néel relaxation loss) rather than the P(Brown relaxation loss) of SPNP agents in nanofluids.

Feasibility of TEOS coated CoFe2O4 nanoparticles to a GMR biosensor agent for single molecular detection.

Magnetic properties of 200 nm ferrimagnetic CoFe2O4 nanoparticles before and after coating with TEOS were explored and compared to soft ferrimagnetic MgFe2O4 nanoparticles (200 nm) to evaluate the feasibility as an in-vitro GMR SV (giant magnetoresistance spin-valve) biosensor agent for single molecular detection (SMD). It was found that the magnetic degradation (or variation) of TEOS coated CoFe2O4 and MgFe2O4 nanoparticles are dominantly affected by the chemical dispersion process, which is carried out in the oleic acid (OA), oleylamine (OL), or OA+OL surfactant, before starting major coating process. In addition, the TEOS coating thickness controlled by TEOS concentration and pH level in the buffer solution prominently influenced on the magnetic degradation of TEOS coated nanoparticles. According to the experimental analysis results, the magnetic degradation of TEOS coated nanoparticles is mainly attributed to the variation of particle dipole interaction caused by the degree of particle aggregation depending on TEOS coating process conditions. The TEOS coated CoFe2O4 nanoparticles exhibited a higher magnetic stability for a GMR biosensor agent, e.g., small variation of remnant magnetization, saturation magnetization and magnetic coercivity, than that of MgFe2O4 nanoparticles at the different coating process conditions. The physical and chemical analysis confirmed that this is primarily due to its higher magnetic anisotropy. The experimentally verified high biocompatibility as well as the stably maintained magnetic properties of TEOS coated CoFe2O4 nanoparticles demonstrate that CoFe2O4 nanoparticles can be considered as one of the promising ferrimagnetic nanoparticle sensor agent for an SMD GMR SV biosensor.

Reliable evaluation method of heating power of magnetic nanofluids to directly predict the tumor temperature during hyperthermia.

Reliable measurement of heating power of magnetic nanofluids (MNs) to accurately predict the AC heat-induction performance in tumors is highly desirable for clinical magnetic nanofluids hyperthermia (MNFH) application because it can save time for screening the performance of newly developed MNFH agent and minimize the over-use of animals dramatically. Here, a bio-mimicking phantom model, called Pseudo-Tumor Environment System (P-TES), biochemically designed by considering the external and internal critical factors related to the complex biological environments is proposed to provide a highly reliable evaluation method of heating performance of MNs for in-vivo MNFH applications. According to the experimentally analyzed results, the heating power of MNs measured using the P-TES is well accorded with the heating temperature measured in the tumors during in-vivo MNFH. This result strongly demonstrates that the proposed P-TES can be recommended as a standardized measurement method of heating performance of MNs for clinical MNFH application.

Concentration-dependent oscillation of specific loss power in magnetic nanofluid hyperthermia.

Magnetic dipole coupling between the colloidal superparamagnetic nanoparticles (SPNPs) depending on the concentration has been paid significant attention due to its critical role in characterizing the Specific Loss Power (SLP) in magnetic nanofluid hyperthermia (MNFH). However, despite immense efforts, the physical mechanism of concentration-dependent SLP change behavior is still poorly understood and some contradictory results have been recently reported. Here, we first report that the SLP of SPNP MNFH agent shows strong concentration-dependent oscillation behavior. According to the experimentally and theoretically analyzed results, the energy competition among the magnetic dipole interaction energy, magnetic potential energy, and exchange energy, was revealed as the main physical reason for the oscillation behavior. Empirically demonstrated new finding and physically established model on the concentration-dependent SLP oscillation behavior is expected to provide biomedically crucial information in determining the critical dose of an agent for clinically safe and highly efficient MNFH in cancer clinics.

Pseudo-single domain colloidal superparamagnetic nanoparticles designed at a physiologically tolerable AC magnetic field for clinically safe hyperthermia.

Magnetic nanofluid hyperthermia (MNFH) with pure superparamagnetic nanoparticles (P-SPNPs) has drawn a huge attraction for cancer treatment modality. However, the low intrinsic loss power (ILP) and attributable degraded-biocompatibility resulting from the use of a heavy dose of P-SPNP agents as well as low heat induction efficiency in biologically safe AC magnetic field (HAC,safe) are challenging for clinical applications. Here, we report an innovatively designed pseudo-single domain-SPNP (PSD-SPNP), which has the same translational advantages as that of conventional P-SPNPs but generates significantly enhanced ILP at HAC,safe. According to the analyzed results, the optimized effective relaxation time, τeff, and magnetic out-of-phase susceptibility, χ'', precisely determined by the particle size at the specific frequency of HAC,safe are the main reasons for the significantly enhanced ILP. Additionally, in vivo MNFH studies with colloidal PSD-SPNPs strongly demonstrated that it can be a promising agent for clinically safe MNFH application with high efficacy.

Giant Magnetic Heat Induction of Magnesium-Doped γ-Fe2 O3 Superparamagnetic Nanoparticles for Completely Killing Tumors.

Magnetic fluid hyperthermia has been recently considered as a Renaissance of cancer treatment modality due to its remarkably low side effects and high treatment efficacy compared to conventional chemotheraphy or radiotheraphy. However, insufficient AC induction heating power at a biological safe range of AC magnetic field (Happl ·fappl < 3.0-5.0 × 109 A m-1 s-1 ), and highly required biocompatibility of superparamagnetic nanoparticle (SPNP) hyperthermia agents are still remained as critical challenges for successful clinical hyperthermia applications. Here, newly developed highly biocompatible magnesium shallow doped γ-Fe2 O3 (Mg0.13 -γFe2 O3 ) SPNPs with exceptionally high intrinsic loss power (ILP) in a range of 14 nH m2 kg-1 , which is an ≈100 times higher than that of commercial Fe3 O4 (Feridex, ILP = 0.15 nH m2 kg-1 ) at Happl ·fappl = 1.23 × 109 A m-1 s-1 are reported. The significantly enhanced heat induction characteristics of Mg0.13 -γFe2 O3 are primarily due to the dramatically enhanced out-of-phase magnetic susceptibility and magnetically tailored AC/DC magnetic softness resulted from the systematically controlled Mg2+ cations distribution and concentrations in octahedral site Fe vacancies of γ-Fe2 O3 instead of well-known Fe3 O4 SPNPs. In vitro and in vivo magnetic hyperthermia studies using Mg0.13 -γFe2 O3 nanofluids are conducted to estimate bioavailability and biofeasibility. Mg0.13 -γFe2 O3 nanofluids show promising hyperthermia effects to completely kill the tumors.

Effects of Recovery Time during Magnetic Nanofluid Hyperthermia on the Induction Behavior and Efficiency of Heat Shock Proteins 72.

In this study, we investigated the effects of recovery time during magnetic nanofluid hyperthermia (MNFH) on the cell death rate and the heat shock proteins 72 (HSP72) induction behavior in retinal ganglion cells (RGCs-5) to provide a possible solution for highly efficient ocular neuroprotection. The recovery time and the heat duration time during MNFH were systematically controlled by changing the duty cycle of alternating current (AC) magnetic field during MNFH. It was clearly observed that the cell death rate and the HSP72 induction rate had a strong dependence on the recovery time and the optimizated recovery time resulted in maximizing the induction efficiency of HSP72. Controlling the recovery time during MNFH affects not only the cell death rate but also HSP72 induction rate. The cell death rate after MNFH was dramatically decreased by increasing the recovery time during MNFH. However, it was also found that the HSP72 induction rate was slightly decreased by increasing the recovery time. These results indicate that applying the appropriate or optimized recovery time during MNFH can improve the induction efficiency of HSP72 by minimizing the cell death caused by cytotoxic effects of heat.

Magnetically softened iron oxide (MSIO) nanofluid and its application to thermally-induced heat shock proteins for ocular neuroprotection.

Magnetically softened iron oxide (MSIO) nanofluid, PEGylated (Mn0.5Zn0.5)Fe2O4, was successfully developed for local induction of heat shock proteins (HSPs) 72 in retinal ganglion cells (RGCs) for ocular neuroprotection. The MSIO nanofluid showed significantly enhanced alternating current (AC) magnetic heat induction characteristics including exceptionally high SLP (Specific Loss Power, > 2000 W/g). This phenomenon was resulted from the dramatically improved AC magnetic softness of MSIO caused by the magnetically tailored Mn(2+) and Zn(2+) distributions in Fe3O4. In addition, the MSIO nanofluid with ultra-thin surface coating layer thickness and high monodispersity allowed for a higher cellular uptake up to a 52.5% with RGCs and enhancing "relaxation power" for higher AC heating capability. The RGCs cultured with MSIO nanofluid successfully induced HSPs 72 by magnetic nanofluid hyperthermia (MNFH). Moreover, it was interestingly observed that systematic control of "AC magnetically-induced heating up rate" reaching to a constant heating temperature of HSPs 72 induction allowed to achieve maximized induction efficiency at the slowest AC heating up rate during MNFH. In addition to in-vitro experimental verification, the studies of MSIO infusion behavior using animal models and a newly designed magnetic coil system demonstrated that the MSIO has promising biotechnical feasibility for thermally-induced HSPs agents in future glaucoma clinics.

The Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Collagenase-Induced Intracerebral Hemorrhage Rat Model.

Intracerebral hemorrhage (ICH) is one of the devastating types of stroke. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have potential benefits in recovery from brain damage following ICH. This study aimed to identify the beneficial effects of hUCB-MSCs and investigate whether they have anti-inflammatory effects on the ICH brain via neurotrophic factors or cytokines. hUCB-MSCs were transplanted into a collagenase-induced ICH rat model. At 2, 9, 16, and 30 days after ICH, rotarod and limb placement tests were performed to measure behavioral outcomes. ICH rats were sacrificed to evaluate the volume of lesion using H&E staining. Immunostaining was performed to investigate neurogenesis, angiogenesis, and anti-apoptosis at 4 weeks after transplantation. Inflammatory factors (TNF-α, COX-2, microglia, and neutrophils) were analyzed by immunofluorescence staining, RT-PCR, and Western blot at 3 days after transplantation. hUCB-MSCs were associated with neurological benefits and reduction in lesion volume. The hUCB-MSCs-treated group tended to reveal high levels of neurogenesis, angiogenesis, and anti-apoptosis (significant for angiogenesis). The expression levels of inflammatory factors tended to be reduced in the hUCB-MSCs-treated group compared with the controls. Our study suggests that hUCB-MSCs may improve neurological outcomes and modulate inflammation-associated immune cells and cytokines in ICH-induced inflammatory responses.

The Unreliability of MTT Assay in the Cytotoxic Test of Primary Cultured Glioblastoma Cells.

MTT assay is commonly used to assess the cellular cytotoxicity caused by anticancer drugs in glioblastomas. However, there have been some reports insisting that MTT assay exhibited non-specific intracellular reduction of tetrazolium which led to underestimated results of cytotoxicity. Here, we examine whether or not MTT assay can lead to incorrect information regarding alcohol-induced cytotoxicity on immortalized and primary glioblastoma cells. MTT assay was applied to assess the ethanol-induced cytotoxicity at various ethanol concentrations. The cellular cytotoxicity induced by different doses of ethanol was analyzed and compared through several cytotoxic assays. Ethanol-induced cytotoxicity observed through MTT assay on both cell types was shown to be ethanol dose-dependent below a 3% concentration. However, the cytotoxicity was shown to be markedly underestimated only in primary cells at a 5% concentration. RT-PCR and Western Blot showed increased expressions of pro-apoptotic proteins and decreased expressions of anti-apoptotic proteins in an ethanol dose-dependent manner in both cell types. Furthermore, we present a possible mechanism for the unreliable result of MTT assay. A high concentration of ethanol induces more severe membrane damage and increased intracellular concentration of NADH in primary cells which enhances the nonspecific reduction of tetrazolium salt. Together, our findings demonstrate that the cytotoxicity on primary cells could inaccurately be assessed when detected through MTT assay. Therefore, a careful interpretation is needed when one would analyze the cytotoxic results of MTT assay, and it is suggested that other assays must be accompanied to produce more reliable and accurate cytotoxic results on primary glioblastoma cells.

Engineered superparamagnetic Mn0.5Zn0.5Fe2O4 nanoparticles as a heat shock protein induction agent for ocular neuroprotection in glaucoma.

Ocular neuroprotection induced by localized heat shock proteins (HSPs) has been paid considerable attention as an efficacious treatment modality for glaucoma. However, the current clinical approaches to induce HSPs in the retinal ganglion cells (RGCs) are limited due to undesirable side effects. Here, we present that the induction of HSPs by local magnetic hyperthermia using engineered superparamagnetic Mn(0.5)Zn(0.5)Fe(2)O(4) nanoparticle agents (EMZF-SPNPAs) with a 5.5 nm mean particle size is promisingly feasible for a physiologically tolerable ocular neuroprotection modality. The sufficiently high specific absorption rate (SAR) (∼256.4 W/g in an agar solution) achieved at the biologically safe range of applied AC magnetic field and frequency as well as the superior biocompatibility of EMZF-SPNPA, which were confirmed from both in-vitro and in-vivo animal pilot studies, allowing it to be considered as a potential localized HSPs agent. Furthermore, the successful demonstration of a newly designed infusion technique, which diffuses the EMZF-SPNPAs through the vitreous body to the retina in a rat eye, more strongly verified the promises of this biotechnical approach to the ocular neuroprotection modality in glaucoma clinics.