Fabrication of monodisperse magnetic nanorods for improving hyperthermia efficacy.

BACKGROUND: Hyperthermia is one of the promising cancer treatment strategies enabled by local heating with the use of tumor-targeting magnetic nanoparticles (MNP) under a non-invasive magnetic field. However, one of the remaining challenges is how to achieve therapeutic levels of heat (without causing damages to regular tissues) in tumors that cannot be effectively treated with anti-tumor drug delivery. RESULTS: In this work, we report a facile method to fabricate magnetic nanorods for hyperthermia by one-step wet chemistry synthesis using 3-Aminopropyltrimethoxysilane (APTMS) as the shape-controlling agent and ferric and ferrous ions as precursors. By adjusting the concentration of APTMS, hydrothermal reaction time, ratios of ferric to ferrous ions, magnetic nanorods with aspect ratios ranging from 4.4 to 7.6 have been produced. At the clinically recommended field strength of 300 Oe (or less) and the frequency of 184 kHz, the specific absorption rate (SAR) of these nanorods is approximately 50 % higher than that of commercial Bionized NanoFerrite particles. CONCLUSIONS: This increase in SAR, especially at low field strengths, is crucial for treating deep tumors, such as pancreatic and rectal cancers, by avoiding the generation of harmful eddy current heating in normal tissues.

Mitigation of eddy current heating during magnetic nanoparticle hyperthermia therapy.

BACKGROUND: Magnetic nanoparticle hyperthermia therapy is a promising technology for cancer treatment, involving delivering magnetic nanoparticles (MNPs) into tumours then activating them using an alternating magnetic field (AMF). The system produces not only a magnetic field, but also an electric field which penetrates normal tissue and induces eddy currents, resulting in unwanted heating of normal tissues. Magnitude of the eddy current depends, in part, on the AMF source and the size of the tissue exposed to the field. The majority of in vivo MNP hyperthermia therapy studies have been performed in small animals, which, due to the spatial distribution of the AMF relative to the size of the animals, do not reveal the potential toxicity of eddy current heating in larger tissues. This has posed a non-trivial challenge for researchers attempting to scale up to clinically relevant volumes of tissue. There is a relative dearth of studies focused on decreasing the maximum temperature resulting from eddy current heating to increase therapeutic ratio. METHODS: This paper presents two simple, clinically applicable techniques for decreasing maximum temperature induced by eddy currents. Computational and experimental results are presented to understand the underlying physics of eddy currents induced in conducting, biological tissues and leverage these insights to mitigate eddy current heating during MNP hyperthermia therapy. RESULTS: Phantom studies show that the displacement and motion techniques reduce maximum temperature due to eddy currents by 74% and 19% in simulation, and by 77% and 33% experimentally. CONCLUSION: Further study is required to optimise these methods for particular scenarios; however, these results suggest larger volumes of tissue could be treated, and/or higher field strengths and frequencies could be used to attain increased MNP heating when these eddy current mitigation techniques are employed.

Design and Assessment of a Novel Biconical Human-Sized Alternating Magnetic Field Coil for MNP Hyperthermia Treatment of Deep-Seated Cancer.

Magnetic nanoparticle (MNP) hyperthermia therapy is a treatment technique that can be used alone or as an adjunct to radiation and/or chemotherapies for killing cancer cells. During treatment, MNPs absorb a part of electromagnetic field (EMF) energy and generate localized heat when subjected to an alternating magnetic field (AMF). The MNP-absorbed EMF energy, which is characterized by a specific absorption rate (SAR), is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. Furthermore, the AMF penetrates inside tissue and induces eddy currents in electrically conducting tissues, which are proportional to the electric field (J = σE). The eddy currents produce Joule heating ( = 0.5·σ·E2) in the normal tissue, the rate of energy transfer to the charge carriers from the applied electric fields. This Joule heating contains only the electric field because the magnetic field is always perpendicular to the velocity of the conduction charges, i.e., it does not produce work on moving charge. Like the SAR due to MNP, the electric field produced by the AMF coil is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. As a result, the Joule heating is directly proportional to the square of the frequency and transmitter current magnitude. Due to the fast decay of magnetic fields from an AMF coil over distance, MNP hyperthermia treatment of deep-seated tumors requires high-magnitude transmitting currents in the coil for clinically achievable MNP distributions in the tumor. This inevitably produces significant Joule heating in the normal tissue and becomes more complicated for a standard MNP hyperthermia approach for deep-seated tumors, such as pancreatic, prostate, liver, lung, ovarian, kidney, and colorectal cancers. This paper presents a novel human-sized AMF coil and MNP hyperthermia system design for safely and effectively treating deep-seated cancers. The proposed design utilizes the spatial distribution of electric and magnetic fields of circular coils. Namely, it first minimizes the SAR due to eddy currents in the normal tissue by moving the conductors away from the tissue (i.e., increasing coils' radii), and second, it increases the magnetic field at the targeted area (z = 0) due to elevated coils (|z| > 0) by increasing the radius of the elevated coils (|z| > 0). This approach is a promising alternative aimed at overcoming the limitation of standard MNP hyperthermia for deep-seated cancers by taking advantage of the transmitter coil's electric and magnetic field distributions in the human body for maximizing AMF in tumor regions and avoiding damage to normal tissue. The human-sized coil's AMF, MNP activation, and eddy current distribution characteristics are investigated for safe and effective treatment of deep-seated tumors using numerical models. Namely, computational results such as AMF, Joule heating SAR, and temperature distributions are presented for a full-body, 3D human model. The SAR and temperature distributions clearly show that the proposed human-sized AMF coil can provide clinically relevant AMF to the region occupied by deep-seated cancers for the application of MNP hyperthermia therapy while causing less Joule heating in the normal tissues than commonly used AMF techniques.

E. coli Phagelysate: A Primer to Enhance Nanoparticles and Drug Deliveries in Tumor.

The tumor microenvironment (TME), where cancer cells reside, plays a crucial role in cancer progression and metastasis. It maintains an immunosuppressive state in many tumors and regulates the differentiation of precursor monocytes into M1 (anti-tumor)- and M2 (pro-tumor)-polarized macrophages, and greatly reduces anticancer drug and nanoparticle delivery. As a result, the effectiveness of recently developed chemo- and/or nanotechnology-mediated immune and magnetic nanoparticle hyperthermia (mNPH) therapies is inhibited significantly. One of the ways to overcome this limitation is to use E. coli phagelysate as a primer to modify the tumor microenvironment by switching tumor-associated M2 macrophages to anti-tumor M1 macrophages, and initiate the infiltration of tumor-associated macrophages (TAMs). Recently, bacteriophages and phage-induced lysed bacteria (bacterial phagelysates-BPLs) have been shown to be capable of modifying the tumor-associated environment. Phage/BPL-coated proteins tend to elicit strong anti-tumor responses from the innate immune system, prompting phagocytosis and cytokine release. It has also been reported that the microenvironments of bacteriophage- and BPL-treated tumors facilitate the conversion of M2-polarized TAMS to a more M1-polarized (tumoricidal) environment post-phage treatment. This paper demonstrates the feasibility and enhanced efficacy of combining E. coli phagelysate (EcPHL) and mNPH, a promising technology for treating cancers, in a rodent model. Specifically, we illustrate the EcPHL vaccination effect on the TME and mNP distribution in Ehrlich adenocarcinoma tumors by providing the tumor growth dynamics and histology (H&E and Prussian blue) distribution of mNP in tumor and normal tissue.

Optical response of magnetic fluorescent microspheres used for force spectroscopy in the evanescent field.

Force spectroscopy based on magnetic tweezers is a powerful technique for manipulating single biomolecules and studying their interactions. The resolution in magnetic probe displacement, however, needs to be commensurate with molecular sizes. To achieve the desirable sensitivity in tracking displacements of the magnetic probe, some recent approaches have combined magnetic tweezers with total internal reflection fluorescence microscopy. In this situation, a typical force probe is a polymer microsphere containing two types of optically active components: a pure absorber (magnetic nanoparticles for providing the pulling force) and a luminophore (semiconducting nanoparticles or organic dyes for fluorescent imaging). To assess the system's capability fully with regard to tracking the position of the force probe with subnanometer accuracy, we developed a body-of-revolution formulation of the method of auxiliary sources (BOR-MAS) to simulate the absorption, scattering, and fluorescence of microscopic spheres in an evanescent electromagnetic field. The theoretical formulation uses the axial symmetry of the system to reduce the dimensionality of the modeling problem and produces excellent agreement with the reported experimental data on forward scattering intensity. Using the BOR-MAS numerical model, we investigated the probe detection sensitivity for a high numerical aperture objective. The analysis of both backscattering and fluorescence observation modes shows that the total intensity of the bead image decays exponentially with the distance from the surface (or the length of a biomolecule). Our investigations demonstrate that the decay lengths of observable optical power are smaller than the penetration depth of the unperturbed excitation evanescent wave. In addition, our numerical modeling results illustrate that the expected sensitivity for the decay length changes with the angle of incidence, tracking the theoretical penetration depth for a two-media model, and is sensitive to the bead size. The BOR-MAS methodology developed in this work for near-field modeling of bead-tracking experiments fully describes the fundamental photonic response of microscopic BOR probes at the subwavelength level and can be used for future improvements in the design of these probes or in the setup of bead-tracking experiments.

Scatterer localization using a left-handed medium.

This paper explores the possibility of using the focusing property of left-handed materials to estimate the location of a visually obscured target. The field scattered by the target and measured on a surface can be considered as incident upon a left-handed half-space and should converge to a point resembling the mirror image of the scatterer's location. The results are obtained using the method of auxiliary sources as adapted to double-negative media. Two-dimensional scattering is considered, either from a single object or from several targets, using pointlike and Gaussian sources of illumination. The method gives reasonable results when the sizes of the scatterers are comparable to the wavelength.

Phenomenological model to fit complex permittivity data of water from radio to optical frequencies.

A general factorized form of the dielectric function together with a fractional model-based parameter estimation method is used to provide an accurate analytical formula for the complex refractive index in water for the frequency range 10(8)-10(16)Hz . The analytical formula is derived using a combination of a microscopic frequency-dependent rational function for adjusting zeros and poles of the dielectric dispersion together with the macroscopic statistical Fermi-Dirac distribution to provide a description of both the real and imaginary parts of the complex permittivity for water. The Fermi-Dirac distribution allows us to model the dramatic reduction in the imaginary part of the permittivity in the visible window of the water spectrum.

Magnetic Heating of Fe-Co Ferrites: Experiments and Modeling.

Magnetic nanoparticle hyperthermia uses magnetically-induced heat to kill cancer cells. In an alternating magnetic field, the induced heat depends strongly on particles' absorption properties. In order to achieve and maintain therapeutic temperatures inside a tumor and to minimize damage to normal tissues due to induced eddy currents, there is a need to develop new magnetic nanoparticles with improved heating characteristics. This paper investigates the magnetic heating properties of composite iron-cobalt ferrite nanoparticles Co x FeII1-x FeIII2O4 with 0≤x≤1. These composite materials are synthesized using a precipitation method. First, the Fe-Co nanoparticle synthesis is described, then their structure, size, magnetic and heating properties are measured and analyzed. The resulting nanoparticles were treated at temperatures 100-600°C in order to study any structural transformations and changes of physical properties. Finally, an empirical model is used to calculate both the nanoparticles' coercivity and their specific absorption rates for different Co concentrations.

Erratum: "Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy" [J. Appl. Phys. 117, 094302 (2015)].

[This corrects the article , PMID: 25825545.].

Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy.

Magnetic nanoparticles (MNPs), referred to as the Dartmouth MNPs, which exhibit high specific absorption rate at low applied field strength have been developed for hyperthermia therapy applications. The MNPs consist of small (2-5 nm) single crystals of gamma-Fe2O3 with saccharide chains implanted in their crystalline structure, forming 20-40 nm flower-like aggregates with a hydrodynamic diameter of 110-120 nm. The MNPs form stable (>12 months) colloidal solutions in water and exhibit no hysteresis under an applied quasistatic magnetic field, and produce a significant amount of heat at field strengths as low as 100 Oe at 99-164 kHz. The MNP heating mechanisms under an alternating magnetic field (AMF) are discussed and analyzed quantitatively based on (a) the calculated multi-scale MNP interactions obtained using a three dimensional numerical model called the method of auxiliary sources, (b) measured MNP frequency spectra, and (c) quantified MNP friction losses based on magneto-viscous theory. The frequency responses and hysteresis curves of the Dartmouth MNPs are measured and compared to the modeled data. The specific absorption rate of the particles is measured at various AMF strengths and frequencies, and compared to commercially available MNPs. The comparisons demonstrate the superior heating properties of the Dartmouth MNPs at low field strengths (<250 Oe). This may extend MNP hyperthermia therapy to deeper tumors that were previously non-viable targets, potentially enabling the treatment of some of the most difficult cancers, such as pancreatic and rectal cancers, without damaging normal tissue.

The Dartmouth Center for Cancer Nanotechnology Excellence: magnetic hyperthermia.

The Dartmouth Center for Cancer Nanotechnology Excellence - one of nine funded by the National Cancer Institute as part of the Alliance for Nanotechnology in Cancer - focuses on the use of magnetic nanoparticles for cancer diagnostics and hyperthermia therapy. It brings together a diverse team of engineers and biomedical researchers with expertise in nanomaterials, molecular targeting, advanced biomedical imaging and translational in vivo studies. The goal of successfully treating cancer is being approached by developing nanoparticles, conjugating them with Fabs, hyperthermia treatment, immunotherapy and sensing treatment response.

Understanding mNP Hyperthermia for cancer treatment at the cellular scale.

The use of magnetic nanoparticles (mNP's) to induce local hyperthermia has been emerging in recent years as a promising cancer therapy, in both a stand-alone and combination treatment setting. Studies have shown that cancer cells associate with, internalize, and aggregate mNP's more preferentially than normal cells. Once the mNP's are delivered inside the cells, a low frequency (30 kHz-300 kHz) alternating electromagnetic field is used to activate the mNP's. The nanoparticles absorb the applied field and provide localized heat generation at nano-micron scales. It has been shown experimentally that mNP's exhibit collective behavior when in close proximity. Although most prevailing mNP heating models assume there is no magnetic interaction between particles, our data suggests that magnetic interaction effects due to mNP aggregation are often significant; In the case of multi-crystal core particles, interaction is guaranteed. To understand the physical phenomena responsible for this effect, we modeled electromagnetic coupling between mNP's in detail. The computational results are validated using data from the literature as well as measurements obtained in our lab. The computational model presented here is based on a method of moments technique and is used to calculate magnetic field distributions on the nanometer scale, both inside and outside the mNP.

Magnetic nanoparticle hyperthermia: Predictive model for temperature distribution.

Magnetic nanoparticle (mNP) hyperthermia is a promising adjuvant cancer therapy. mNP's are delivered intravenously or directly into a tumor, and excited by applying an alternating magnetic field (AMF). The mNP's are, in many cases, sequestered by cells and packed into endosomes. The proximity of the mNP's has a strong influence on their ability to heat due to inter-particle magnetic interaction effects. This is an important point to take into account when modeling the mNP's. Generally, more mNP heating can be achieved using higher magnetic field strengths. The factor which limits the maximum field strength applied to clinically relevant volumes of tissue is the heating caused by eddy currents, which are induced in the noncancerous tissue. A coupled electromagnetic and thermal model has been developed to predict dynamic thermal distributions during AMF treatment. The EM model is based on the method of auxiliary sources and the thermal modeling is based on the Pennes bioheat equation. The results of our phantom study are used to validate the model which takes into account nanoparticle heating, interaction effects, particle spatial distribution, particle size distribution, EM field distribution, and eddy current generation in a controlled environment. Preliminary in vivo data for model validation are also presented. Once fully developed and validated, the model will have applications in experimental design, AMF coil design, and treatment planning.

Surface wave multipath signals in near-field microwave imaging.

Microwave imaging techniques are prone to signal corruption from unwanted multipath signals. Near-field systems are especially vulnerable because signals can scatter and reflect from structural objects within or on the boundary of the imaging zone. These issues are further exacerbated when surface waves are generated with the potential of propagating along the transmitting and receiving antenna feed lines and other low-loss paths. In this paper, we analyze the contributions of multi-path signals arising from surface wave effects. Specifically, experiments were conducted with a near-field microwave imaging array positioned at variable heights from the floor of a coupling fluid tank. Antenna arrays with different feed line lengths in the fluid were also evaluated. The results show that surface waves corrupt the received signals over the longest transmission distances across the measurement array. However, the surface wave effects can be eliminated provided the feed line lengths are sufficiently long independently of the distance of the transmitting/receiving antenna tips from the imaging tank floor. Theoretical predictions confirm the experimental observations.

Quantitative modeling of forces in electromagnetic tweezers.

This paper discusses numerical simulations of the magnetic field produced by an electromagnet for generation of forces on superparamagnetic microspheres used in manipulation of single molecules or cells. Single molecule force spectroscopy based on magnetic tweezers can be used in applications that require parallel readout of biopolymer stretching or biomolecular binding. The magnetic tweezers exert forces on the surface-immobilized macromolecule by pulling a magnetic bead attached to the free end of the molecule in the direction of the field gradient. In a typical force spectroscopy experiment, the pulling forces can range between subpiconewton to tens of piconewtons. In order to effectively provide such forces, an understanding of the source of the magnetic field is required as the first step in the design of force spectroscopy systems. In this study, we use a numerical technique, the method of auxiliary sources, to investigate the influence of electromagnet geometry and material parameters of the magnetic core on the magnetic forces pulling the target beads in the area of interest. The close proximity of the area of interest to the magnet body results in deviations from intuitive relations between magnet size and pulling force, as well as in the force decay with distance. We discuss the benefits and drawbacks of various geometric modifications affecting the magnitude and spatial distribution of forces achievable with an electromagnet.

Characterization of an Implicitly Resistively-Loaded Monopole Antenna in Lossy Liquid Media.

Microwave tomographic imaging of the breast for cancer detection is a topic of considerable interest because of the potential to exploit the apparent high-dielectric property contrast between normal and malignant tissue. An important component in the realization of an imaging system is the antenna array to be used for signal transmission/detection. The monopole antenna has proven to be useful in our implementation because it can be easily and accurately modeled and can be positioned in close proximity to the imaging target with high-element density when configured in an imaging array. Its frequency response is broadened considerably when radiating in the liquid medium that is used to couple the signals into the breast making it suitable for broadband spectral imaging. However, at higher frequencies, the beam patterns steer further away from the desired horizontal plane and can cause unwanted multipath contributions when located in close proximity to the liquid/air interface. In this paper, we have studied the behavior of these antennas and devised strategies for their effective use at higher frequencies, especially when positioned near the surface of the coupling fluid which is used. The results show that frequencies in excess of 2 GHz can be used when the antenna centers are located as close as 2 cm from the liquid surface.