Applied Alternating Magnetic Field Research Articles

Development of handheld induction heaters for magnetic fluid hyperthermia applications and in-vitro evaluation on ovarian and prostate cancer cell lines

Objective: Magnetic fluid hyperthermia (MFH) is a still experimental technique found to have a potential application in the treatment of cancer. The method aims to reach around 41 °C–47 °C in the tumor site by exciting magnetic nanoparticles with an externally applied alternating magnetic field (AMF), where cell death is expected to occur. Applying AMFs with high spatial resolution is still a challenge. The AMFs from current and prospective MFH applicators cover relatively large areas; being not suitable for patients having metallic implants near the treatment area. Thus, there will be a clinical need for smaller magnetic field applicators. To this end, a laparoscopic induction heater (LIH) and a transrectal induction heater (TRIH) were developed. Methods: Miniature ‘pancake’ coils were wound and inserted into 3D printed enclosures. Ovarian (SKOV-3, A2780) and prostate (PC-3, LNCaP) cancer cell lines were used to evaluate the instruments’ capabilities in killing cancer cells in vitro, using Synomag®-D nanoparticles as the heat mediators. NIH3T3 normal cell lines were also used with both devices to observe if these cells tolerated the conditions applied. Results: Magnetic field intensities reached by the LIH and TRIH were 42.6 kA m−1 at 326 kHz and 26.3 kA m−1 at 303 kHz, respectively. Temperatures reached in the samples were 41 °C by the LIH and 43 °C by the TRIH. Both instruments successfully accomplished killing cancer cells, with minimal effects on normal cells. Conclusion: This work presents the first line of handheld medical induction heaters and have the potential to be a complement to existing cancer therapies. Significance: These instruments could enable the development of MFH modalities that will facilitate the clinical translation of this thermal treatment.

Symbiotic thermo-chemotherapy for enhanced HepG2 cancer treatment via magneto-drugs encapsulated polymeric nanocarriers

The existence of cancer and its continuous threat to life demands extensive therapeutic research. Moreover, there has been a drastic increment in newer cancer cases every year around the world, which advocates a unique way of improving cancer treatments. Recently, magnetic fluid hyperthermia (MFH) has received significant attention in cancer nano-therapeutics, and it allows us to be symbiotically utilized with other modalities such as chemotherapy to enhance treatment efficacies. However, numerous challenges must be needed to overcome in clinical hyperthermia scenarios such as higher heat-inducing property & therapeutic efficacy with (i) minimal concentration of therapeutic agents to prevent acute toxicity, and also (ii) tolerable MFH strength & frequency to evade needless side effects on the patients. To address these current challenges, in this work superparamagnetic iron oxide nanoparticles (SPIONs) and dual-drugs (nifedipine (a calcium channel blocker) & curcumin) are co-encapsulated in a step-wise manner inside d-ɑ-tocopheryl polyethylene glycol succinate (TPGS)-stabilized poly(d,l-lactide-co-glycolide) (PLGA-a polymeric nanocarrier) nanoparticles (TP-NPs). Herein, significant attention has been given to balancing both the safety and therapeutic effectiveness by optimizing the concentrations of dual drugs, SPIONs & also nanocarriers (i.e., TP-NPs), and also applied alternating magnetic field (AMF). The SPIONs inside TP-NPs have exhibited improved magneto-thermal effects (i.e., measured in terms of specific absorption rate (SAR) = 62.8–72.0 W/gFe) under an applied AMF. As a result of these improved effects via SPIONs, dual drugs are effectively released (almost ∼90 % in a time-dependent manner) and concentrated highly inside the HepG2 cancer cells. Consequently, the in vitro thermo-chemotherapy studies have shown enhanced inhibition rates (up to 89 %) in the growth of HepG2 cancer cells at a very less concentration (i.e., 0.5 mgFe). The results obtained from the present study are compared with previous reports, which have indicated that magneto-drugs encapsulated polymeric nanocarriers (i.e, TP-NPs) prepared in this work are highly promising in improving the cancer treatment efficacy by producing an extensive symbiotic effect.

Targeted destruction of cancer stem cells using multifunctional magnetic nanoparticles that enable combined hyperthermia and chemotherapy.

Cancer stem cells (CSCs) have been implicated in cancer recurrence and therapy resistance. Therefore, a CSC-targeted therapy that disrupts the maintenance and survival of CSCs may offer an effective approach in killing tumor cells in primary tumors and preventing the metastasis caused by CSCs. Nanoparticles (NPs)-based thermotherapy and/or chemotherapy are promising therapeutic methods for cancer treatment.Methods: A silica-based multifunctional NP system was present, which encapsulated a chemotherapeutic agent and magnetic cores and coated with a specific antibody against the lung CSCs. The efficacy of this novel therapeutic strategy was systematically studied both in vitro and in vivo by simultaneous activating the combined thermotherapy and chemotherapy via CSC-targeted NPs.Results: These NPs were systematically administered and activated for targeted chemotherapy and thermotherapy by using an externally applied alternating magnetic field (AMF). The antibody-modified NPs targeted to lung CSCs with enhanced cellular uptake in vitro and extended accumulation in tumor in vivo. Up to 98% of lung CSCs was killed in vitro with 30-min application of AMF, due to the combined effects of hyperthermia and chemotherapeutic drug treatment. In in vivo models, this combined therapy significantly suppressed tumor growth and metastasis in lung CSC xenograft-bearing mice, with minimal side effects and adverse effects.Conclusion: With good biocompatibility and targeting capability, the nanodrug delivery system may offer a promising clinical platform for the combined thermotherapy and chemotherapy. This work demonstrated the feasibility of developing multifunctional nanomedicine targeting CSCs for effective cancer treatment.

Effects of particle diameter and magnetocrystalline anisotropy on magnetic relaxation and magnetic particle imaging performance of magnetic nanoparticles

The dynamic magnetization of immobilized spherical single-domain magnetic nanoparticles (MNPs) with uniaxial or cubic magnetocrystalline anisotropy was studied computationally by executing simulations based on the Landau–Lifshitz–Gilbert (LLG) equation. For situations when a static magnetic field was suddenly applied and then removed, the effects of particle diameter and anisotropy (considering both type of symmetry and characteristic energy) on the characteristic magnetic relaxation time were studied parametrically. The results, for both anisotropy symmetries, show that when a static magnetic field is suddenly turned on or off the MNPs undergo a successive two-step or combined one-step relaxation. Whether a MNP relaxes with one or two steps when the field is turned on is determined by the competition between the energy of the applied magnetic field, the magnetic anisotropy energy, and thermal energy. When the applied magnetic field is suddenly turned off, our results show good agreement with theoretical predictions for the cases of and , where represents the magnetic anisotropy energy barrier, is the Boltzmann constant and represents the absolute temperature. For the case of an applied alternating magnetic field (AMF) that is typical of magnetic particle imaging (MPI) applications, the effects of particle diameter and anisotropy symmetry were studied in terms of time-domain magnetization dynamics, dynamic hysteresis loops, harmonic spectra, and x-space point spread functions (PSFs). Results illustrate that the type of magnetocrystalline anisotropy (uniaxial versus cubic) has a significant effect on the MPI performance of the nanoparticles. These computational studies provide insight into the role of particle diameter and magnetic anisotropy on the performance of MNPs for applications in magnetorelaxometry and MPI.

In-gel study of the effect of magnetic nanoparticles immobilization on their heating efficiency for application in Magnetic Fluid Hyperthermia

Abstract Recent studies on magnetic nanoparticles (MNPs) used for Magnetic Fluid Hyperthermia treatments have shown that Brownian rotation is suppressed when they are confined within a cell. To investigate this effect we conducted a systematic study of the Specific Absorption Rate (SAR) of colloidal suspensions of MNPs in water and gels at different agarose concentration. SAR measurements were conducted by varying the frequency (f = 110–990 kHz) and amplitude (up to 17 kA/m) of the applied alternating magnetic field (AMF). MNP samples with different diameter (d = 10, 14, and 18 nm) were used. Our results show that Neel relaxation dominates SAR with negligible contribution from Brownian motion for smaller MNPs (d = 10 nm). For the largest MNPs (d = 18 nm) we observed a more significant SAR decrease in gel suspensions as compared to those in solution. In particular, when applying AMFs as the ones used in a clinical setting (16.2 kA/m at f = 110 kHz), we measured SAR value of 67 W/g in solution and 25 W/g in gel. This experimental finding demonstrates that investigation of MNPs properties should be conducted in media with viscosity similar to the one found in mammalian tissues.

Examining the effect of ions and proteins on the heat dissipation of iron oxide nanocrystals.

In this paper, the effect and contribution of physiological components like ions and proteins under an applied alternating magnetic field (AMF) towards heat dissipation of superparamagnetic iron oxide nanoparticles (SPIONs) are discussed. Our results have shown that under an applied AMF, magnetic hyperthermia efficiency could be significantly enhanced if SPIONs were suspended in 1× phosphate buffered saline (PBS) compared to a suspension in de-ionized (DI) water. However, no heat enhancement was found when SPIONs were suspended in blood which is an amalgamation of physiological ions and proteins. Closer investigations have revealed that the presence of physiological ions can contribute positively to heating efficiency, and the heating efficiency increases with concentration of ions, ionic mass and solubility. However, the heating efficiency of ions can be suppressed to an insignificant level (comparable with measurement error), in the presence of physiological proteins in 1×PBS. Our electrochemical studies also showed that ionic mobility can be reduced significantly if proteins were present in the solution, thus retarding the heating efficiency.

Thermosensitive gemcitabine-magnetoliposomes for combined hyperthermia and chemotherapy

The combination of magnetic hyperthermia therapy with the controlled release of chemotherapeutic agents in tumors may be an efficient therapeutic with few side effects because the bioavailability, tolerance and amount of the drug can be optimized. Here, we prepared magnetoliposomes consisting of magnetite nanoparticle cores and the anticancer drug gemcitabine encapsulated by a phospholipid bilayer. The potential of these magnetoliposomes for controlled drug release and cancer treatment via hyperthermic behavior was investigated. The magnetic nanoparticle encapsulation efficiency was dependent on the initial amount of magnetite nanoparticles present at the encapsulation stage; the best formulation was 66%. We chose this formulation to characterize the physicochemical properties of the magnetoliposomes and to encapsulate gemcitabine. The mean particle size and distribution were determined by dynamic light scattering (DLS), and the zeta potential was measured. The magnetoliposome formulations all had acceptable characteristics for systemic administration, with a mean size of approximately 150 nm and a polydispersity index <0.2. The magnetoliposomes were stable in aqueous suspension for at least one week, as determined by DLS. Temperature increases due to the dissipation energy of magnetoliposome suspensions subjected to an applied alternating magnetic field (AMF) were measured at different magnetic field intensities, and the values were appropriated for cancer treatments. The drug release profile at 37 °C showed that 17% of the gemcitabine was released after 72 h. Drug release from magnetoliposomes exposed to an AMF for 5 min reached 70%.

Magnetic Nanoparticles with High Specific Absorption Rate at Low Alternating Magnetic Field.

This paper describes the synthesis and properties of a new type of magnetic nanoparticle (MNP) for use in the hyperthermia treatment of tumors. These particles consist of 2-4 nm crystals of gamma-Fe2O3 gathered in 20-40 nm aggregates with a coating of carboxymethyl-dextran, producing a zetasize of 110-120 nm. Despite their very low saturation magnetization (1.5-6.5 emu/g), the specific absorption rate (SAR) of the nanoparticles is 22-200 W/g at applied alternating magnetic field (AMF) with strengths of 100-500 Oe at a frequency of 160 kHz.

Monodispersed magnetite nanoparticles optimized for magnetic fluid hyperthermia: Implications in biological systems

Magnetite (Fe(3)O(4)) nanoparticles (MNPs) are suitable materials for Magnetic Fluid Hyperthermia (MFH), provided their size is carefully tailored to the applied alternating magnetic field (AMF) frequency. Since aqueous synthesis routes produce polydisperse MNPs that are not tailored for any specific AMF frequency, we have developed a comprehensive protocol for synthesizing highly monodispersed MNPs in organic solvents, specifically tailored for our field conditions (f = 376 kHz, H(0) = 13.4 kA∕m) and subsequently transferred them to water using a biocompatible amphiphilic polymer. These MNPs (σ(avg.) = 0.175) show truly size-dependent heating rates, indicated by a sharp peak in the specific loss power (SLP, W∕g Fe(3)O(4)) for 16 nm (diameter) particles. For broader size distributions (σ(avg.) = 0.266), we observe a 30% drop in overall SLP. Furthermore, heating measurements in biological medium [Dulbecco's modified Eagle medium (DMEM) + 10% fetal bovine serum] show a significant drop for SLP (∼30% reduction in 16 nm MNPs). Dynamic Light Scattering (DLS) measurements show particle hydrodynamic size increases over time once dispersed in DMEM, indicating particle agglomeration. Since the effective magnetic relaxation time of MNPs is determined by fractional contribution of the Neel (independent of hydrodynamic size) and Brownian (dependent on hydrodynamic size) components, we conclude that agglomeration in biological medium modifies the Brownian contribution and thus the net heating capacity of MNPs.

Short Communication: Nanoparticle Thermotherapy and External Beam Radiation Therapy for Human Prostate Cancer Cells

Nanoparticle thermotherapy (NPTT) uses monoclonal antibody-linked iron oxide magnetic nanoparticles (bioprobes) for the tumor-specific thermotherapy of cancer by hysteretic heating of the magnetic component of the probes through an externally applied alternating magnetic field (AMF). The present study investigated the effect of NPTT on a human prostate cancer cell line, DU145. The concept of total heat dose (THD) as a measure for NPTT was validated on a cellular level and THD was correlated to cell death in vitro. The study, furthermore, explored the potential enhancement of the NPTT effect through added external beam radiation therapy (EBRT), because both forms of treatment have a different, and potentially complementary, mechanism of causing cell death. Using carbodiimide, (111)In-DOTA-ChL6 was conjugated to dextran iron oxide 20-nm particles with polyethylene glycol COOH groups on the surface and purified as (111)In-bioprobes. NPTT and EBRT were applied alone and combined to cells labeled with the bioprobes. Cell response was monitored by measuring lactate dehydrogenase (LDH), a product of cytolysis, in the medium. This distinct focus on the response to NPTT was possible, since we found in previous studies that the LDH assay was relatively insensitive to the response of cells (without bioprobes) to EBRT in the dose levels given here. NPTT showed a significantly increased cell death at a total calculated heat dose of 14.51 and 29.02 J/g cells (50% and 100% AMF duty, 350 Oe, 136 kHz, 12 cycles, 20 minutes total), compared with AMF exposure in the absence of bioprobes. Adding EBRT to NPTT did not increase cell death, as measured by LDH. However, EBRT given to cells labeled with bioprobes caused significant cell death at radiation doses of 10 Gy and higher. In human prostate cancer cell cultures, NPTT applied as a single modality caused cell death that correlated with THD estimation; complete cell death occurred at 14.51 J/g cells. Consequently, enhancement of the NPTT effect through the addition of EBRT could not be addressed. Interestingly, EBRT induced cell death on bioprobe-labeled cells at EBRT levels that did not show cell death in the absence of bioprobes; this phenomenon is worth investigating further.

Development of Multivalent Radioimmunonanoparticles for Cancer Imaging and Therapy

Noninvasive, focused hyperthermia can be achieved by using an externally applied alternating magnetic field (AMF) if effective concentrations of nanoparticles can be delivered to the target cancer cells. Targeting agents, for example, monoclonal antibodies or peptides, linked to magnetic iron oxide nanoparticles (NP), represent a promising strategy to target cancer cells and hyperthermia. We have developed a new radioconjugate NP ((111)In-DOTA-di-scFv-NP), using recombinantly generated antibody fragments, di-scFv-c, for the imaging and therapy of anti-MUC-1-expressing cancers, because aberrant MUC-1 is abundantly expressed on the majority of human epithelial cancers. Anti-MUC-1 di-scFv-c (50 kDa) were engineered, generated, and selected to link maleimide functionalized nanoparticles (NP-M). DOTA chelate was conjugated with di-scFv-c for radionuclide chelation to trace the radioimmunonanoparticles (RINPs) in vivo. Heat-inducing NP-M were prepared with maleimide density >15 per particle for site-specific thiolation. The specific activity of the RINP was 4-5 microCi (111)In/mg with >10 molecules of di-scFv per NP. We characterized the RINP by polyacrylamide gel electrophoresis, cellulose acetate electrophoresis, size-exclusion chromatography, and tumor-cell binding. RINP had a >90% di-scFv conjugated to NP and an immunoreactivity >80% relative to unmodified di-scFv-c on HBT 3477 and DU145 tumor cells. Pharmacokinetics and whole-body autoradiography studies demonstrated that a 5% injected dose was targeted in tumor after 24 hours. Further development of this new preparation of RINP may provide uniquely high tumor-targeting NP for AMF-driven tumor hyperthermia with less spleen and kidney accumulation.

Development of Tumor Targeting Bioprobes (111In-Chimeric L6 Monoclonal Antibody Nanoparticles) for Alternating Magnetic Field Cancer Therapy

(111)In-chimeric L6 (ChL6) monoclonal antibody (mAb)-linked iron oxide nanoparticle (bioprobes) pharmacokinetics, tumor uptake, and the therapeutic effect of inductively heating these bioprobes by externally applied alternating magnetic field (AMF) were studied in athymic mice bearing human breast cancer HBT 3477 xenografts. Tumor cell radioimmunotargeting of the bioprobes and therapeutic and toxic responses were determined. Using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl, (111)In-7,10-tetra-azacyclododecane-N, N',N'',N'''-tetraacetic acid-ChL6 was conjugated to the carboxylated polyethylene glycol on dextran-coated iron oxide 20 nm particles, one to two mAbs per nanoparticle. After magnetic purification and sterile filtration, pharmacokinetics, histopathology, and AMF/bioprobe therapy were done using (111)In-ChL6 bioprobe doses (20 ng/2.2 mg ChL6/ bioprobe), i.v. with 50 microg ChL6 in athymic mice bearing HBT 3477; a 153 kHz AMF was given 72 hours postinjection for therapy with amplitudes of 1,300, 1,000, or 700 Oe. Weights, blood counts, and tumor size were monitored and compared with control mice receiving nothing, or AMF or bioprobes alone. (111)In-ChL6 bioprobe binding in vitro to HBT 3477 cells was 50% to 70% of that of (111)In-ChL6. At 48 hours, tumor, lung, kidney, and marrow uptakes of the (111)In-ChL6 bioprobes were not different from that observed in prior studies of (111)In-ChL6. Significant therapeutic responses from AMF/bioprobe therapy were shown with up to eight times longer mean time to quintuple tumor volume with therapy compared with no treatment (P = 0.0013). Toxicity was only seen in the 1,300 Oe AMF cohort, with 4 of 12 immediate deaths and skin erythema. Electron micrographs showed bioprobes on the surfaces of the HBT 3477 cells of excised tumors and tumor necrosis 24 hours after AMF/bioprobe therapy. This study shows that mAb-conjugated nanoparticles (bioprobes), when given i.v., escape into the extravascular space and bind to cancer cell membrane antigen, so that bioprobes can be used in concert with externally applied AMF to deliver thermoablative cancer therapy.