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BACKGROUND: Magnetic Fluid Hyperthermia (MFH) is a promising adjuvant for chemotherapy, potentiating the action of anticancer agents. However, drug delivery to cancer cells must be optimized to improve the overall therapeutic effect of drug/MFH combination treatments. PURPOSE: The aim of this work was to demonstrate the potentiation of 2-phenylethynesulfonamide (PES) at various combination treatments with MFH, using low-intensity ultrasound as an intracellular delivery enhancer. METHODS: The effect of ultrasound (US), MFH, and PES was first evaluated individually and then as combination treatments. Definity® microbubbles and polyethylene glycol (PEG)-coated iron oxide nanoparticles were used to induce cell sonoporation and MFH, respectively. Assessment of cell membrane permeabilization was evaluated via fluorescence microscopy, iron uptake by cells was quantified by UV-Vis spectroscopy, and cell viability was determined using automatic cell counting. RESULTS: Notable reductions in cancer cell viability were observed when ultrasound was incorporated. For example, the treatment US+PES reduced cell viability by 37% compared to the non-toxic effect of the drug. Similarly, the treatment US+MFH using mild hyperthermia (41°C), reduced cell viability by an additional 18% when compared to the effect of MH alone. Significant improvements were observed for the combination of US+PES+MFH with cell viability reduced by an additional 26% compared to the PES+MFH group. The improved cytotoxicity was attributed to enhanced drug/nanoparticle intracellular delivery, with iron uptake values nearly twice those achieved without ultrasound. Various treatment schedules were examined, and all of them showed substantial cell death, indicating that the time elapsed between sonoporation and magnetic field exposure was not significant. CONCLUSION: Superior cancer cell-killing patterns took place when ultrasound was incorporated thus demonstrating the in vitro ultrasonic potentiation of PES and mild MFH. This work demonstrated that ultrasound is a promising non-invasive enhancer of PES/MFH combination treatments, aiming to establish a sono-thermo-chemotherapy in the treatment of ovarian cancer.

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Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calculated for PES treatment reporting a synergistic effect. In vivo efficacy experiments with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly reduction in tumor growth rate was observed with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 intraperitoneal tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966-76. ©2017 AACR.

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Nanomaterials are the subject of intense research, focused on their synthesis, modification, and biomedical applications. Increased nanomaterial production and their wide range of applications imply a higher risk of human and environmental exposure. Unfortunately, neither environmental effects nor toxicity of nanomaterials to organisms are fully understood. Cost-effective, rapid toxicity assays requiring minimal amounts of materials are needed to establish both their biomedical potential and environmental safety standards. Drosophila exemplifies an efficient and cost-effective model organism with a vast repertoire of in vivo tools and techniques, all with high-throughput scalability and screening feasibility throughout its life cycle. Here we report tissue specific nanomaterial assessment through direct microtransfer into target tissues. We tested several nanomaterials with potential biomedical applications such as single-wall carbon nanotubes, multiwall carbon nanotubes, silver, gold, titanium dioxide, and iron oxide nanoparticles. Assessment of nanomaterial toxicity was conducted by evaluating progression through developmental morphological milestones in Drosophila. This cost-effective assessment method is amenable to high-throughput screening.

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The proteasome inhibitor bortezomib (BZ) has shown promising results in some types of cancer, but in others it has had minimal activity. Recent studies have reported enhanced efficacy of BZ when combined with hyperthermia. However, the use of magnetic nanoparticles to induce hyperthermia in combination with BZ has not been reported. This novel hyperthermia modality has shown better potentiation of chemotherapeutics over other types of hyperthermia. We hypothesized that inducing hyperthermia via magnetic nanoparticles (MFH) would enhance the cytotoxicity of BZ in BZ-sensitive and BZ-resistant cancer cells more effectively than hyperthermia using a hot water bath (HWH). Studies were conducted using BZ in combination with MFH in two BZ-sensitive cell lines (MDA-MB-468, Caco-2), and one BZ-resistant cell line (A2780) at two different conditions, ie, 43°C for 30 minutes and 45°C for 30 minutes. These experiments were compared with combined application of HWH and BZ. The results indicate enhanced potentiation between hyperthermic treatment and BZ. MFH combined with BZ induced cytotoxicity in sensitive and resistant cell lines to a greater extent than HWH under the same treatment conditions. The observation that MFH sensitizes BZ-resistant cell lines makes this approach a potentially effective anticancer therapy platform.

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Clinical studies have demonstrated the effectiveness of hyperthermia as an adjuvant for chemotherapy and radiotherapy. However, significant clinical challenges have been encountered, such as a broader spectrum of toxicity, lack of patient tolerance, temperature control and significant invasiveness. Hyperthermia induced by magnetic nanoparticles in high-frequency oscillating magnetic fields, commonly termed magnetic fluid hyperthermia, is a promising form of heat delivery in which thermal energy is supplied at the nanoscale to the tumor. This review discusses the mechanisms of heat dissipation of iron oxide-based magnetic nanoparticles, current methods and challenges to deliver heat in the clinic, and the current work related to the use of magnetic nanoparticles for the thermal-chemopotentiation of therapeutic drugs.

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Iron oxide nanoparticles were coated with the biocompatible, biodegradable, non-immunogenic polysaccharide inulin by introduction of carboxyl groups into the inulin structure and conjugation with amine groups on the surface of iron oxide nanoparticles grafted with 3-aminopropyltriethoxysilane. The resulting nanoparticles were characterized by FT-IR spectroscopy, transmission electron microscopy, dynamic light scattering, zeta potential, SQUID magnetometry, and with respect to their energy dissipation rate in applied alternating magnetic fields. The nanoparticles had a hydrodynamic diameter in the range of 70 ± 10 nm and were superparamagnetic, with energy dissipation rates in the range of 58-175 W/g for an applied field frequency of 233 kHz and an applied field amplitude in the range of 20-48 kA/m. The nanoparticles were stable in a range of pH, at temperatures between 23°C and 53°C, and in short term storage in water, PBS, and culture media. The particles were non-cytotoxic to the immortalized human cancer cell lines Hey A8 FDR, A2780, MDA 468, MCF-7 and Caco-2. The nanoparticles were readily taken up by Caco-2 cells in a time and concentration dependent fashion, and were found to have a pharmacokinetic time constant of 47 ± 3 min. The small size, non-cytotoxicity, and efficient energy dissipation of the particles could make them useful for biomedical applications such as magnetic fluid hyperthermia.

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Magnetic fluid hyperthermia as a cancer treatment method is an attractive alternative to other forms of hyperthermia. It is based on the heat released by magnetic nanoparticles subjected to an alternating magnetic field. Recent studies have shown that magnetic fluid hyperthermia-treated cells respond significantly better to chemotherapeutic treatment compared with cells treated with hot water hyperthermia under the same temperature conditions. We hypothesized that this synergistic effect is due to an additional stress on the cellular membrane, independent of the thermal heat dose effect that is induced by nanoparticles exposed to an alternating magnetic field. This would result in an increase in Cis-diammine-dichloroplatinum (II) (cDDP, cisplatin) uptake via passive transport. To test this hypothesis, we exposed cDDP-treated cells to extracellular copper in order to hinder the human cell copper transporter (hCTR1)-mediated active transport of cDDP. This, in turn, can increase the passive transport of the drug through the cell membrane. Our results did not show statistically significant differences in surviving fractions for cells treated concomitantly with magnetic fluid hyperthermia and cDDP, in the presence or absence of copper. Nonetheless, significant copper-dependent variations in cell survival were observed for samples treated with combined cDDP and hot water hyperthermia. These results correlated with platinum uptake studies, which showed that cells treated with magnetic fluid hyperthermia had higher platinum uptake than cells treated with hot water hyperthermia. Changes in membrane fluidity were tested through fluorescence anisotropy measurements using trimethylamine-diphenylhexatriene. Additional uptake studies were conducted with acridine orange and measured by flow cytometry. These studies indicated that magnetic fluid hyperthermia significantly increases cell membrane fluidity relative to hot water hyperthermia and untreated cells, and hence this could be a factor contributing to the increase of cDDP uptake in magnetic fluid hyperthermia-treated cells. Overall, our data provide convincing evidence that cell membrane permeability induced by magnetic fluid hyperthermia is significantly greater than that induced by hot water hyperthermia under similar temperature conditions, and is at least one of the mechanisms responsible for potentiation of cDDP by magnetic fluid hyperthermia in Caco-2 cells.

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This study was conducted to evaluate the effect of commercially available engineered iron oxide nanoparticles coated with a surfactant (ENP(Fe-surf)) on effluent water quality from a lab-scale sequencing batch reactor as a model secondary biological wastewater treatment. Results showed that ~8.7% of ENP(Fe-surf) applied were present in the effluent stream. The stable presence of ENP(Fe-surf) was confirmed by analyzing the mean particle diameter and iron concentration in the effluent. Consequently, aqueous ENP(Fe-surf) deteriorated the effluent water quality at a statistically significant level (p < 0.05) with respect to soluble chemical oxygen demand, turbidity, and apparent color. This implied that ENP(Fe-surf) would be introduced into environmental receptors through the treated effluent and could potentially impact them.

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It is currently believed that magnetic nanoparticle heaters (MNHs) can kill cancer cells only when the temperature is raised above 43 °C due to energy dissipation in an alternating magnetic field. On the other hand, simple heat conduction arguments indicate that in small tumors or single cells the relative rates of energy dissipation and heat conduction result in a negligible temperature rise, thus limiting the potential of MNHs in treating small tumors and metastatic cancer. Here we demonstrate that internalized MNHs conjugated to epidermal growth factor (EGF) and which target the epidermal growth factor receptor (EGFR) do result in a significant (up to 99.9%) reduction in cell viability and clonogenic survival in a thermal heat dose dependent manner, without the need for a perceptible temperature rise. The effect appears to be cell type specific and indicates that magnetic nanoparticles in alternating magnetic fields may effectively kill cancer cells under conditions previously considered as not possible.

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Colloidal suspensions of iron oxide magnetic nanoparticles are known to dissipate energy when exposed to an oscillating magnetic field. Such energy dissipation can be employed to locally raise temperature inside a tumor between 41°C and 45°C (hyperthermia) to promote cell death, a treatment known as magnetic fluid hyperthermia (MFH). This work seeks to quantify differences between MFH and hot-water hyperthermia (HWH) in terms of reduction in cell viability using two cancer cell culture models, Caco-2 (human epithelial colorectal adenocarcinoma) and MCF-7 (human breast cancer). Magnetite nanoparticles were synthesized via the co-precipitation method and functionalized with adsorbed carboxymethyl dextran. Cytotoxicity studies indicated that in the absence of an oscillating magnetic field, cell viability was not affected at concentrations of up to 0.6 mg iron oxide/mL. MFH resulted in a significant decrease in cell viability when exposed to a magnetic field for 120 minutes and allowed to rest for 48 hours, compared with similar field applications, but with shorter resting time. The results presented here suggest that MFH most likely induces apoptosis in both cell types. When compared with HWH, MFH produced a significant reduction in cell viability, and these effects appear to be cell-type related.

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Methods of predicting temperature profiles during local hyperthermia treatment are very important to avoid damage to healthy tissue. With this aim, fundamental solutions of Pennes' bioheat equation are derived in rectangular, cylindrical, and spherical coordinates. The medium is idealised as isotropic with effective thermal properties. Temperature distributions due to space- and time-dependent heat sources are obtained by the solution method presented. Applications of the fundamental solutions are addressed with emphasis on a particular problem of Magnetic Fluid Hyperthermia (MFH) consisting of a thin shell of magnetic nanoparticles in the outer surface of a spherical solid tumour. It is observed from the solution of this particular problem that the temperature profiles are strongly dependent on the distribution of the magnetic nanoparticles within the tissue. An almost uniform temperature profile is obtained inside the tumour with little penetration of therapeutic temperatures to the outer region of healthy tissue. The fundamental solutions obtained can be used to develop boundary element methods to predict temperature profiles with more complicated geometries.

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Both fully dispersed unpolarized and polarized chemiluminescence spectra from the Ba((3)P)+N(2)O reaction have been recorded under hyperthermal laser-ablated atomic beam-Maxwellian gas conditions at three specific average collision energies E(c) in the range of 4.82-7.47 eV. A comprehensive analysis of the whole data series suggests that the A (1)Sigma(+)-->X (1)Sigma(+) band system dominates the chemiluminescence. The polarization results revealed that the BaO(A (1)Sigma(+)) product rotational alignment is insensitive to its vibrational state upsilon(') at E(c)=4.82 eV but develops into an strong negative correlation between product rotational alignment and upsilon(') at 7.47 eV. The results are interpreted in terms of a direct mechanism involving a short-range, partial electron transfer from Ba((3)P) to N(2)O which is constrained by the duration of the collision, so that the reaction has a larger probability to occur when the collision time is larger than the time needed for N(2)O bending. The latter in turn determines that, at any given E(c), collinear reactive intermediates are preferentially involved when the highest velocity components of the corresponding collision energy distributions are sampled. Moreover, the data at 4.82 eV suggest that a potential barrier to reaction which favors charge transfer to bent N(2)O at chiefly coplanar geometries is operative for most of the reactive trajectories that sample the lowest velocity components. Such a barrier would arise from the relevant ionic-covalent curve crossings occurring in the repulsive region of the covalent potential Ba((3)P)cdots, three dots, centeredN(2)O((1)Sigma(+)); from this crossing the BaO(A (1)Sigma(+)) product may be reached through mixings in the exit channel with potential energy surfaces leading most likely to the spin-allowed b (3)Pi and a (3)Sigma(+) products. The variation with increasing E(c) of both the magnitude of the average BaO(A (1)Sigma(+)) rotational alignment and the BaO(A (1)Sigma(+)) rovibrational excitation, as obtained from spectral simulations of the unpolarized chemiluminescence spectra, consistently points to additional dynamic factors, most likely the development of induced repulsive energy release as the major responsible for the angular momentum and energy disposal at the two higher E(c) studied. The results of a simplified version of the direct interaction with product repulsion-distributed as in photodissociation model do not agree with the observed average product rotational alignments, showing that a more realistic potential energy surface model will be necessary to explain the present results.

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Nanoparticle systems are an intense subject of research for various biomedical applications. Colloidal suspensions of magnetic nanoparticles are of special interest, particularly in bioimaging, and more recently, in Magnetic Fluid Hyperthermia (MFH). MFH promises to be a viable alternative in the treatment of localized cancerous tumors. The treatment consists of locally injecting magnetic nanoparticles in fluid suspension into the tumor site and exposing the site to an oscillating magnetic field, where nanoparticles dissipate energy in the form of heat, causing a localized rise in temperature and tumor cell death. Here we will review methods of magnetic nanoparticle synthesis, and the role of the nanoparticle surface coating in achieving colloidal stability, minimizing toxicity, and targeting. Finally, we review in vitro and in vivo MFH experiments, and clinical studies in the treatment of glioblastoma multiforme and prostate cancer.

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Monodisperse magnetite nanoparticles modified with poly(ethylene glycol) (PEG) were synthesized using a silane functionalized PEG obtained by reacting 3-aminopropyl triethoxysilane with carboxylic acid-methoxy PEG (mPEG-COOH) using amide reactions. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential measurements show the particles are monodisperse (sigma(gv) approximately 0.2) and stable in water for pH of 3-9 and ionic strengths, up to 0.3 M NaCl. Thermogravimetric analysis coupled with TEM and DLS indicates formation of a dense graft layer on the particle surface. An analysis of the interparticle interaction energy indicates that the particles are stabilized by strong steric repulsions between PEG chains on their surface.

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The temperature dependence of the state-to-state vibrational relaxation rate constant (k(nu)(21-Delta nu)) for collisions between I(2)(B,nu(')=21) and He at very low kinetic energies was studied. The fluorescence from I(2)(B,nu(')=21-Delta nu(')) with Delta nu(')=1-5 indicates that in the temperature range of 0.6-8.2 K these states are populated by only one collision with He. The behavior of k(nu)(21-Delta nu) with temperature can be divided into two groups. The group with quantum changes Delta nu(')=1-3 shows scattering resonances in the low temperature region, with a general monotonical decrease of the rate constant with temperature, suggesting the importance of van der Waals interactions. This behavior is supported by the calculation of the probability of tunneling through the centrifugal barriers. For collisions in which 4-5 quanta are lost in a single event, there are no evidences of scattering resonances and the values of the relaxation rate constants could be determined only at the highest temperatures of this study. This suggests that relaxation occurs via impulsive collisions. The branching ratios for each channel are also temperature dependent and this behavior also suggests that the energy transfer mechanism changes with Delta nu(').

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The chemiluminescent reaction Ba(6s6p (3)P)+N(2)O was studied at an average collision energy of 1.56 eV in a beam-gas arrangement. Ba((3)P) was produced by laser ablation of barium, which resulted in a broad collision energy distribution extending up to approximately 5.7 eV. A series of experiments was made to extract the Ba((3)P) contribution to chemiluminescence from that corresponding to Ba 6s(2) (1)S0 and 6s5d (3)D, which are the other two most populated states in the atomic beam. The fully dispersed polarized chemiluminescence spectra at 400-600 nm from the title reaction were recorded and assigned to a BaO molecule excited in the A (1)Sigma+ level. In addition, the average and wavelength-resolved degrees of polarization associated to the parallel BaO(A (1)Sigma+-->X (1)Sigma+) emission are reported. The analysis of the average polarization degree show that the BaO(A (1)Sigma+) product is significantly aligned, suggesting that the reaction mechanism is predominantly direct. The product rotational alignment was found to depend markedly on the emission wavelength, which revealed a negative correlation with the BaO(A (1)Sigma+) product vibrational state. On the basis of experimental and theoretical investigations on the reactions of N(2)O with both the (1)S0, (3)D, and (1)P1 states of Ba and the lighter group 2 atoms, it is suggested that the Ba((3)P) reaction involves a charge transfer at relatively short reagent separations and that restricted collision geometries at the highest velocity components of the broad distribution are necessary to rationalize the data.

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We present an analytical procedure based on laser ablation mass spectrometry (LAMS) in order to detect and quantify arsenic and calcium in soil samples and we analyze the diverse factors that influence the precision of LAMS, such as laser fluence and matrix effect. The results indicate that a Zn matrix is a good choice for the analysis of those metals in soil samples. This work also provides a method for the direct determination of As in soil samples whose concentrations are lower than 100 ppm with a 70 ppm minimum detection limits (MDL).