Hyperthermia Studies Research Articles

Heating Induced by Therapeutic Ultrasound in the Presence of Magnetic Nanoparticles.

The efficiency of ultrasound hyperthermia for anti-cancer treatments such as radiotherapy or chemotherapy can be improved by using sonosensitizers, which are materials that enhance the attenuation and dissipation of acoustic energy. We propose the use of magnetic nanoparticles as sonosensitizers because of their biocompatibility, nontoxicity, and common use in several medical applications. A magnetic material was synthetized and then incorporated in the form of a magnetic fluid in agar tissue-mimicking phantoms. Ultrasound hyperthermia studies were conducted at various ultrasound frequencies and concentrations of magnetic nanoparticles in the phantoms. The theoretical modeling based on a heat transfer equation and the experimental results show good agreement and confirm that the temperature rise during ultrasound heating in tissue-mimicking phantoms doped with sonosensitizers is greater than that in a pure agar phantom. Furthermore, on the basis of Pennes' bio-heat equation, which takes into consideration the blood perfusion and metabolic heat, the thermal dose and lesion shapes after sonication were determined for a hypothetical tissue.

Dynamical Magnetic Response of Iron Oxide Nanoparticles Inside Live Cells.

Magnetic nanoparticles exposed to alternating magnetic fields have shown a great potential acting as magnetic hyperthermia mediators for cancer treatment. However, a dramatic and unexplained reduction of the nanoparticle magnetic heating efficiency has been evidenced when nanoparticles are located inside cells or tissues. Recent studies suggest the enhancement of nanoparticle clustering and/or immobilization after interaction with cells as possible causes, although a quantitative description of the influence of biological matrices on the magnetic response of magnetic nanoparticles under AC magnetic fields is still lacking. Here, we studied the effect of cell internalization on the dynamical magnetic response of iron oxide nanoparticles (IONPs). AC magnetometry and magnetic susceptibility measurements of two magnetic core sizes (11 and 21 nm) underscored differences in the dynamical magnetic response following cell uptake with effects more pronounced for larger sizes. Two methodologies have been employed for experimentally determining the magnetic heat losses of magnetic nanoparticles inside live cells without risking their viability as well as the suitability of magnetic nanostructures for in vitro hyperthermia studies. Our experimental results-supported by theoretical calculations-reveal that the enhancement of intracellular IONP clustering mainly drives the cell internalization effects rather than intracellular IONP immobilization. Understanding the effects related to the nanoparticle transit into live cells on their magnetic response will allow the design of nanostructures containing magnetic nanoparticles whose dynamical magnetic response will remain invariable in any biological environments, allowing sustained and predictable in vivo heating efficiency.

A Novel Approach for Determining the Electromagnetic Properties of a Colloidal Fluid With Magnetic Nanoparticles for Hyperthermia Applications

The paper presents a general analytical method for evaluating the magnetic properties of colloidal fluid with magnetic nanoparticles and agar through in vitro specific absorption rate (SAR) measurements. The approach for the determination of magnetic complex susceptibility herein presented reveals itself as simple, rapid, broadband, and accurate enough to compete with alternative conventional direct methods requiring complex and expensive instrumentation. In particular, it makes use of indirect equations based on the single-order Debye model [linear response theory (LRT)] combined with a punctual set of in vitro SAR measurements. The procedure is effective inside the range of validity of the LRT theory, and it can be easily applied in the up-growing field of magnetic hyperthermia studies.

Systematic magnetic fluid hyperthermia studies of carboxyl functionalized hydrophilic superparamagnetic iron oxide nanoparticles based ferrofluids

We have systematically studied heating efficiencies (via specific absorption rate–SAR/intrinsic loss power-ILP) of carboxyl (terephthalic acid-TA) functionalized hydrophilic SPIONs based ferrofluids (with good biocompatibility/high magnetization) and influence of following key factors in magnetic fluid hyperthermia (MFH): (i) alternating magnetic fields (AMFs - H)/frequencies (f) - chosen below/above Hergt’s biological safety limit, (ii) concentrations (0.5–8 mg/ml) and (iii) dispersion media (water, a cell-culture medium and triethylene glycol (TEG)) for in vitro cancer therapy. In calorimetric MFH, aqueous ferrofluids have displayed excellent time-dependent temperature rise for the applied AMFs, which resulted in high SAR ranging from 23.4 to 160.7 W/gFe, attributed to the enhanced magnetic responses via π-conjugations of short-chained TA molecules on the surface of SPIONs. Moreover, ILP values up-to 2.5 nHm2/kg (higher than the best commercial ferrofluids) are attained for the aqueous ferrofluids when excited below the recommended safety limit. Besides, the SPIONs dispersed in high viscous TEG have exhibited the highest SAR value (178.8 W/gFe) and reached therapeutic temperatures at faster rates for the lowest concentration due to prominent Neel relaxations. Moreover, these SPIONs have higher killing efficiency towards MCF-7 cancer cells in in vitro studies. Thus, the TA-based ferrofluids have great potential for in vivo/clinical MFH cancer therapies.

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.

Conventional and microwave combustion synthesis of optomagnetic CuFe2O4 nanoparticles for hyperthermia studies

Nanosized copper ferrite (CuFe2O4) nanoparticles have been prepared by conventional (CCM) and microwave (MCM) combustion methods using Hibiscus rosa sinensis plant extract as a fuel. XRD and rietveld analysis confirmed the formation of single cubic phase and with crystallite size varying from 25 to 62 nm owing to grain growth after calcination. FT-IR analysis confirms the modes of the cubic CuFe2O4 phase, due to the stretching and bending vibrations. Spherical shaped particles are observed by scanning electron microscopy and the average particle size is found to be in the range of 50–200 nm. The chemical composition is confirmed by energy dispersive X-ray analysis. The optical band gap energy estimated using Kubelka-Munk function with the help of UV–Visible diffused reflectance spectroscopy, is found to be 2.34 and 2.22 eV for CCM and MCM respectively. Photoluminescence analysis indicates that both samples absorb light in the UV–visible region and exhibit emissions at 360, 376, and 412 nm. Magnetic measurements indicate a ferromagnetic behavior, where both magnetic properties very much influenced by the preparation method and calcination temperature: both saturation magnetization and coercivity are found higher when using CCM and MCM; from 29.40 to 34.09 emu/g while almost double from 224.4 to 432.2 Oe. The observed changes in physical properties are mainly associated with crystallinity, particle size, better chemical homogeneity, and cations distribution among tetrahedral/octahedral sites. The maximum specific absorption rate obtained was 14.63 W/g, which can be considered suitable and favorable for magnetic hyperthermia. This study highlighted the benefits of green synthesis of CuFe2O4 nanoparticles providing better magnetic properties for the platform of hyperthermia application.

Hydroxyapatite Coated Iron Oxide Nanoparticles: A Promising Nanomaterial for Magnetic Hyperthermia Cancer Treatment.

Targeting cancer cells without injuring normal cells is the prime objective in treatment of cancer. In this present study, solvothermal and wet chemical precipitation techniques were employed to synthesize iron oxide (IO), hydroxyapatite (HAp), and hydroxyapatite coated iron oxide (IO-HAp) nanoparticles for magnetic hyperthermia mediated cancer therapy. The synthesized well dispersed spherical IO-HAp nanoparticles, magnetite, and apatite phases were confirmed by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) and Field emission transmission electron microscopy (FETEM) with Energy Dispersive X-ray spectroscopy (EDS). The non-toxic behavior of synthesized IO-HAp nanoparticles was confirmed by cytotoxicity assay (Trypan blue and MTT assay). The synthesized nanoparticles revealed a remarkable magnetic saturation of 83.2 emu/g for IO and 40.6 emu/g for IO-HAp nanoparticles in presence of 15,000 Oe (1.5 T) magnetic field at room temperature (300 K). The magnetic hyperthermia study that was performed with IO-HAp nanoparticles showed an excellent hyperthermia effect (SAR value 85 W/g) over MG-63 osteosarcoma cells. The in vitro hyperthermia temperature (~45 °C) was reached within 3 min, which shows a very high efficiency and kills nearly all of the experimental MG-63 osteosarcoma cells within 30 min exposure. These results could potentially open new perceptions for biomaterials that are aimed for anti-cancer therapies based on magnetic hyperthermia.

Multifunctional PEG-carboxylate copolymer coated superparamagnetic iron oxide nanoparticles for biomedical application

Biocompatible magnetite nanoparticles (MNPs) were prepared by post-coating the magnetic nanocores with a synthetic polymer designed specifically to shield the particles from non-specific interaction with cells. Poly(ethylene glycol) methyl ether methacrylate (PEGMA) macromonomers and acrylic acid (AA) small molecular monomers were chemically coupled by quasi-living atom transfer radical polymerization (ATRP) to a comb-like copolymer, P(PEGMA-co-AA) designated here as P(PEGMA-AA). The polymer contains pendant carboxylate moieties near the backbone and PEG side chains. It is able to bind spontaneously to MNPs; stabilize the particles electrostatically via the carboxylate moieties and sterically via the PEG moieties; provide high protein repellency via the structured PEG layer; and anchor bioactive proteins via peptide bond formation with the free carboxylate groups. The presence of the P(PEGMA-AA) coating was verified in XPS experiments. The electrosteric (i.e., combined electrostatic and steric) stabilization is efficient down to pH 4 (at 10 mM ionic strength). Static magnetization and AC susceptibility measurements showed that the P(PEGMA-AA)@MNPs are superparamagnetic with a saturation magnetization value of 55 emu/g and that both single core nanoparticles and multicore structures are present in the samples. The multicore components make our product well suited for magnetic hyperthermia applications (SAR values up to 17.44 W/g). In vitro biocompatibility, cell internalization, and magnetic hyperthermia studies demonstrate the excellent theranostic potential of our product.

The effect of interparticle interactions on spin glass and hyperthermia properties of Fe3O4 nanoparticles

Water dispersible Fe3O4 nanoparticles (NPs) were prepared, forming a durable suspension for several days. The zero field cooled magnetization peak temperature is ~4.5 times larger than the average blocking temperature, suggesting the presence of interparticle interactions. Frequency dependent AC magnetic susceptibility revealed superspin glass state at low temperatures. Also a signature of size dependent surface spin glass state was observed associated with a hump in in-phase and a peak in out-of phase susceptibility curves. Magnetic hyperthermia studies indicated that interparticle interactions influence the heat generation of NPs in an AC magnetic field. The temperature rise of 7 nm particles obtained was 8 times larger than that of 5 nm particles. This study shows the important role of interparticle interactions on magnetic and hyperthermia properties of magnetic NPs.

Hyperthermia studies using inductive and ultrasound methods on E. coli bacteria and mouse glioma cells

The survival of Escherichia coli bacteria and mouse glioma cells were studied under different temperatures using direct heating in water, ultrasound, and magnetic fluid hyperthermia. The survival of these microorganisms depended on whether the heating mode was continuous or discontinuous, surviving more in the former than in the discontinuous heating mode. Whereas Escherichia coli bacteria did not survive at temperatures ≥50∘C, the mouse glioma cells did not survive at temperatures ≥48∘C. The survival of both these microorganisms was independent of the presence or absence of the magnetic nanoparticles of magnetite, suggesting that these, having mean particle sizes of 9.5, 8.5 and 5, did not show any apparent cytotoxicity effect. Present results also showed that the inductive heating system which used a radiofrequency of 13.56 MHz, providing a maximum magnetic field strength of 160 A/m, the electric rather than magnetic heating predominated.

Proton Relaxivity and Magnetic Hyperthermia Evaluation of Gadolinium Doped Nickel Ferrite Nanoparticles as Potential Theranostic Agents.

This paper outlines the preparation of gadolinium doped nickel ferrite nanoparticles as potential magnetic carriers and longitudinal magnetic resonance imaging contrast agents using hydrothermal method with gadolinium concentration varying from 10% to 40%. A concise effect on the crystal structure was observed at 10% and 20% gadolinium doping, while gadolinium oxide was observed to leach at concentrations exceeding 20%. Further, gadolinium doped nickel ferrites were analyzed for their morphological, magnetic, proton relaxation and magnetic hyperthermia heating properties to understand their potential role as magnetic carrier agents. Low temperature and room temperature magnetic studies conducted on the samples showed comparatively high magnetic saturation with low remanent magnetization. Further, relaxometry studies revealed a high relaxation rate of 6.63 s−1 at a concentration of 0.1 mg/mL. Magnetic hyperthermia studies of the samples at a concentration of 1 mg/mL, assessed that the samples attained a temperature of 68 °C in 240 seconds.

Structure characterization of the magnetosome solutions for hyperthermia study

Structure characterization of the initial magnetosome chain solution (IM) and mechanically treated magnetosome solution (SM) was conducted by dynamic light scattering (DLS), small-angle neutron (SANS) and X-ray (SAXS) scattering. Experimental scattering curves of magnetosome IM and SM samples indicate the presence of polydisperse particles in the investigated solutions. Predominant amount of non-magnetic components (most probably lipids) was found from SANS contrast variation experiment. The values of forward scattering intensities confirm the differences in average sizes of samples prepared by various methods. The effect of sonication and filtering on size distribution and polydispersity was also confirmed by evaluating of hydrodynamic size distribution. This fact causes that SM sample magnetically behaves in a different manner showing that energy losses and specific absorption rate are noticeable reduced, and that indicates variation in the relaxation process and heat distribution.

Synthesis and magnetic properties of gadolinium substituted zinc ferrites

Gadolinium-doped zinc ferrite nanoparticles were synthesized using standard co-precipitation method. The samples were annealed at 1200°C to form crystalline composites. Gadolinium concentration in the precursor solution was varied from 10% to 40% with respect to iron concentration. The particles were observed to have an average particle size of 100nm by scanning electron microscope. X-ray diffraction analysis revealed significant change in the crystal structure from the cubic spinel to orthorhombic by changing gadolinium concentration from 10% to 40%. Formation of mixed phases of orthorhombic and cubic spinel gadolinium zinc iron oxides was observed. The ferromagnetic properties of the samples decreased with increasing gadolinium doping resulting in antiferromagnetic nature at 40% gadolinium concentration. Magnetic hyperthermia studies confirmed a high heating rate for samples with 20% and 30% gadolinium doping which suggest their use in cancer therapy.

Magnetic hyperthermia study in water based magnetic fluids containing TMAOH coated Fe3O4 using infrared thermography

We study the alternating magnetic field induced heating of a water based ferrofluid containing tetramethyl ammonium hydroxide coated iron oxide nanoparticles using infrared thermography and compare the results obtained from the conventional fiber optic temperature sensor. Experiments are performed on ferrofluid samples of five different concentrations and under four different external field amplitudes at a fixed frequency. The temperature rise curves measured using both the infrared thermography and fiber optic sensor are found to be very similar up to a certain time interval, above which deviations are observed, which are attributed to the internal and external convection phenomena. A correction methodology is developed to account for the convection losses. The convection corrected specific absorption rate is found to be in good agreement with the values obtained from the conventional fiber optic temperature sensor, within a maximum error of ±3.4%. The highest specific absorption rate obtained in the present study is 135.98 (±4.6)W/gFe for a sample concentration of 3wt.%, at an external field amplitude and a frequency of 63.0kAm−1 and 126kHz, respectively. The specific absorption rate is found to decrease with increasing sample concentration, due to the enhancement of dipolar interaction with increasing sample concentration due to agglomeration. This study validates the efficacy and universal applicability of IRT as an alternate, real time, non-contact and wide area temperature measurement methodology for magnetic fluid hyperthermia experiments without any sample contamination.

Theranostic Nanocages for Imaging and Photothermal Therapy of Prostate Cancer Cells by Active Targeting of Neuropeptide-Y Receptor.

Gold nanocages (AuNCs) have been shown to be a useful tool for harnessing imaging and hyperthermia therapy of cancer, thanks to their unique optical properties, low toxicity, and facile surface functionalization. Herein, we use AuNCs for selective targeting of prostate cancer cells (PC3) via specific interaction between neuropeptide Y (NPY) receptor and three different NPY analogs conjugated to AuNCs. Localized surface plasmon resonance band of the nanoconjugates was set around 800 nm, which is appropriate for in vivo applications. Long-term stability of nanoconjugates in different media was confirmed by UV-vis and DLS studies. Active NPY receptor targeting was observed by confocal microscopy showing time-dependent AuNCs cellular uptake. Activation of ERK1/2 pathway was evaluated by Western blot to confirm the receptor-mediated specific interaction with PC3. Cellular uptake kinetics were compared as a function of peptide structure. Cytotoxicity of nanoconjugates was evaluated by MTS and Annexin V assays, confirming their safety within the concentration range explored. Hyperthermia studies were carried out irradiating the cells, previously incubated with AuNCs, with a pulsed laser at 800 nm wavelength, showing a heating enhancement ranging from 6 to 35 °C above the culture temperature dependent on the irradiation power (between 1.6 and 12.7 W/cm2). Only cells treated with AuNCs underwent morphological alterations in the cytoskeleton structure upon laser irradiation, leading to membrane blebbing and loss of microvilli associated with cell migration. This effect is promising in view of possible inhibition of proliferation and invasion of cancer cells. In summary, our Au-peptide NCs proved to be an efficient theranostic nanosystem for targeted detection and activatable killing of prostate cancer cells.

Magnetic hyperthermia in solid magnetic colloids

Abstract We present results of theoretical study of magnetic hyperthermia in systems of single-domain ferromagnetic particles homogeneously distributed in a solid matrix. The heat effect is induced by linearly polarized alternating magnetic field. The effect of magnetic interaction between the particles as well as influence of orientation of the particles magnetic axes are in a focus of our consideration. Analysis shows that the interparticle interaction increases intensity of the heat production. The thermal effect in the systems with parallel orientation of the particles axes of easy magnetization is significantly higher than that in the case of random orientation of these axes.

Plasmonic/Magnetic Multifunctional nanoplatform for Cancer Theranostics.

A multifunctional magneto-plasmonic CoFe2O4@Au core-shell nanoparticle was developed by iterative-seeding based method. This nanocargo consists of a cobalt ferrite kernel as a core (Nk) and multiple layers of gold as a functionalizable active stratum, (named as Nk@A after fifth iteration). Nk@A helps in augmenting the physiological stability and enhancing surface plasmon resonance (SPR) property. The targeted delivery of Doxorubicin using Nk@A as a nanopayload is demonstrated in this report. The drug release profile followed first order rate kinetics optimally at pH 5.4, which is considered as an endosomal pH of cells. The cellular MR imaging showed that Nk@A is an efficient T2 contrast agent for both L6 (r2-118.08 mM−1s−1) and Hep2 (r2-217.24 mM−1s−1) cells. Microwave based magnetic hyperthermia studies exhibited an augmentation in the temperature due to the transformation of radiation energy into heat at 2.45 GHz. There was an enhancement in cancer cell cytotoxicity when hyperthermia combined with chemotherapy. Hence, this single nanoplatform can deliver 3-pronged theranostic applications viz., targeted drug-delivery, T2 MR imaging and hyperthermia.

A computational study of cancer hyperthermia based on vascular magnetic nanoconstructs.

The application of hyperthermia to cancer treatment is studied using a novel model arising from the fundamental principles of flow, mass and heat transport in biological tissues. The model is defined at the scale of the tumour microenvironment and an advanced computational scheme called the embedded multiscale method is adopted to solve the governing equations. More precisely, this approach involves modelling capillaries as one-dimensional channels carrying flow, and special mathematical operators are used to model their interaction with the surrounding tissue. The proposed computational scheme is used to analyse hyperthermic treatment of cancer based on systemically injected vascular magnetic nanoconstructs carrying super-paramagnetic iron oxide nanoparticles. An alternating magnetic field is used to excite the nanoconstructs and generate localized heat within the tissue. The proposed model is particularly adequate for this application, since it has a unique capability of incorporating microvasculature configurations based on physiological data combined with coupled capillary flow, interstitial filtration and heat transfer. A virtual tumour model is initialized and the spatio-temporal distribution of nanoconstructs in the vascular network is analysed. In particular, for a reference iron oxide concentration, temperature maps of several different hypothesized treatments are generated in the virtual tumour model. The observations of the current study might in future guide the design of more efficient treatments for cancer hyperthermia.

Infrared thermography based magnetic hyperthermia study in Fe3O4 based magnetic fluids

Owing to the immense clinical benefits, magnetic hyperthermia is likely to emerge as an alternate cancer therapeutic procedure in the near future. Presently, radio frequency immune fiber optic based sensors are being used to monitor temperature changes during magnetic hyperthermia measurements, which have inherent limitations due to the requirement of physical contact of the sensor with the sample, contamination and temperature monitoring at a single point. Here, we investigate the field induced heating of oil based oleic acid coated Fe3O4 nanofluid, synthesized using co-precipitation method, using infrared thermal imaging (IRT) camera and compare the results with those of fiber optic temperature sensor. Experiments were performed on nanofluid samples of four different concentrations and under five different external field amplitudes. The specific absorption rate (SAR) of the samples were determined from the initial rate of temperature rise measured using both the techniques. The SAR values determined from both the techniques were in very good agreement with each other, with in an accuracy of 5%, after incorporating convection loss correction on the infrared thermal imaging data. The consecutive thermal cycling on the samples showed good thermal stability and thermal recovery. The maximum SAR obtained was 95.9W/gFe for a sample concentration and field amplitude of 23wt.% and 57.3kAm−1, respectively. This study showed the efficacy and accuracy of temperature measurement using IRT during field induced heating of magnetic nanofluid and its advantages over conventional point measurements techniques for real-time, non-contact and wide area temperature mapping without sample contamination.

Cancer Hyperthermia Studies: On the Aqueous Structure and Radiofrequency-Induced Heating Properties of a Water-Soluble [60]Fullerene

The symmetrical, malonodiserinolamide hexa-substituted [60]fullerene, C60-ser, is a key water-soluble C60 derivative of interest for the treatment of cancer by radiofrequency(RF)-induced hyperthermia due to its biocompatibility, neutral charge, lipophilicity, and ability to cross restrictive biological membranes. In aqueous solution C60-ser, which is surrounded by 24 hydroxyl groups, maintains relatively stable layers of closely-bound water molecules (hydration sphere), forms highly dynamic aggregates, sized between 100-400 nm in diameter, which exist in equilibrium with individual, hydrated C60-ser molecules. Our recent observations indicate that these dynamic C60-ser aggregates are built up of a single layer of C60-ser molecules, with water locked inside a hollow core structure. Using a thermal imaging camera, aqueous C60-ser solutions have been shown to produce heat when irradiated with an 13.56 MHz RF field (900W) in a concentration-dependent manner with a heating rate of up to 1.0 °C/sec at 10 mg/ml. This result establishes that C60-ser is a neutrally-charged, key [60]fullerene-based nanoparticle, that might be used for the treatment of cancer by RFH-induced hyperthermia. We acknowledge Kanzius Foundation and Welch Foundation Grant C-0627 for financial support. Figure 1