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1.  Development of Novel Magnetic Nanoparticles for Hyperthermia Cancer Therapy 
Proceedings of SPIE  2011;7901:790115-.
Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe3O4) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe3O4 with superior SAR values.
doi:10.1117/12.876514
PMCID: PMC3947375  PMID: 24619487
Magnetic Nanoparticle; Ferrofluid; Hyperthermia; Tumor; Cancer; Synthesis
2.  Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma 
Background
We have developed magnetite cationic liposomes (MCLs) and applied them to local hyperthermia as a mediator. MCLs have a positive charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. In this study, the effect of hyperthermia using MCLs was examined in an in vivo study of hamster osteosarcoma.
Method
MCLs were injected into the osteosarcoma and then subjected to an AMF.
Results
The tumor was heated at over 42°C, but other normal tissues were not heated as much. Complete regression was observed in 100% of the treated group hamsters, whereas no regression was observed in the control group hamsters. At day 12, the average tumor volume of the treated hamsters was about 1/1000 of that of the control hamsters. In the treated hamsters, no regrowth of osteosarcomas was observed over a period of 3 months after the complete regression.
Conclusion
These results suggest that this treatment is effective for osteosarcoma.
doi:10.1186/1477-044X-2-3
PMCID: PMC400754  PMID: 15040804
3.  Hyperthermic treatment of DMBA-induced rat mammary cancer using magnetic nanoparticles 
Background
We have developed magnetite cationic liposomes (MCLs) and applied them as a mediator of local hyperthermia. MCLs can generate heat under an alternating magnetic field (AMF). In this study, the in vivo effect of hyperthermia mediated by MCLs was examined using 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer as a spontaneous cancer model.
Method
MCLs were injected into the mammary cancer and then subjected to an AMF.
Results
Four rats in 20 developed mammary tumors at more than 1 site in the body. The first-developed tumor in each of these 4 rats was selected and heated to over 43°C following administration of MCLs by an infusion pump. After a series of 3 hyperthermia treatments, treated tumors in 3 of the 4 rats were well controlled over a 30-day observation period. One of the 4 rats exhibited regrowth after 2 weeks. In this rat, there were 3 sites of tumor regrowth. Two of these regrowths were reduced in volume and regressed completely after 31 days, although the remaining one grew rapidly. These results indicated hyperthermia-induced immunological antitumor activity mediated by the MCLs.
Conclusion
Our results suggest that hyperthermic treatment using MCLs is effective in a spontaneous cancer model.
doi:10.1186/1477-044X-6-2
PMCID: PMC2266920  PMID: 18298831
4.  Intratumoral Iron Oxide Nanoparticle Hyperthermia and Radiation Cancer Treatment 
The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model.
Methods
MTG-B murine breast cancer cells (1 × 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/− 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period.
Results
Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than nonnanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure.
doi:10.1117/12.706302
PMCID: PMC4187389  PMID: 25301985
5.  Structural properties of magnetic nanoparticles determine their heating behavior - an estimation of the in vivo heating potential 
Nanoscale Research Letters  2014;9(1):602.
Magnetically induced heating of magnetic nanoparticles (MNP) in an alternating magnetic field (AMF) is a promising minimally invasive tool for localized tumor treatment by sensitizing or killing tumor cells with the help of thermal stress. Therefore, the selection of MNP exhibiting a sufficient heating capacity (specific absorption rate, SAR) to achieve satisfactory temperatures in vivo is necessary. Up to now, the SAR of MNP is mainly determined using ferrofluidic suspensions and may distinctly differ from the SAR in vivo due to immobilization of MNP in tissues and cells. The aim of our investigations was to study the correlation between the SAR and the degree of MNP immobilization in dependence of their physicochemical features.
In this study, the included MNP exhibited varying physicochemical properties and were either made up of single cores or multicores. Whereas the single core MNP exhibited a core size of approximately 15 nm, the multicore MNP consisted of multiple smaller single cores (5 to 15 nm) with 65 to 175 nm diameter in total. Furthermore, different MNP coatings, including dimercaptosuccinic acid (DMSA), polyacrylic acid (PAA), polyethylenglycol (PEG), and starch, wereinvestigated. SAR values were determined after the suspension of MNP in water. MNP immobilization in tissues was simulated with 1% agarose gels and 10% polyvinyl alcohol (PVA) hydrogels.
The highest SAR values were observed in ferrofluidic suspensions, whereas a strong reduction of the SAR after the immobilization of MNP with PVA was found. Generally, PVA embedment led to a higher immobilization of MNP compared to immobilization in agarose gels. The investigated single core MNP exhibited higher SAR values than the multicore MNP of the same core size within the used magnetic field parameters. Multicore MNP manufactured via different synthesis routes (fluidMAG-D, fluidMAG/12-D) showed different SAR although they exhibited comparable core and hydrodynamic sizes. Additionally, no correlation between ζ-potential and SAR values after immobilization was observed.
Our data show that immobilization of MNP, independent of their physicochemical properties, can distinctly affect their SAR. Similar processes are supposed to take place in vivo, particularly when MNP are immobilized in cells and tissues. This aspect should be adequately considered when determining the SAR of MNP for magnetic hyperthermia.
doi:10.1186/1556-276X-9-602
PMCID: PMC4230907  PMID: 25404872
Immobilization; Specific absorption rate (SAR); Intrinsic loss power (ILP); Magnetic nanoparticles (MNP); Magnetic hyperthermia
6.  Tailored Magnetic Nanoparticles for Optimizing Magnetic Fluid Hyperthermia 
Magnetic Fluid Hyperthermia (MFH) is a promising approach towards adjuvant cancer therapy that is based on the localized heating of tumors using the relaxation losses of iron oxide magnetic nanoparticles (MNPs) in alternating magnetic fields (AMF). In this study, we demonstrate optimization of MFH by tailoring MNP size to an applied AMF frequency. Unlike conventional aqueous synthesis routes, we use organic synthesis routes that offer precise control over MNP size (diameter ~ 10–25 nm), size distribution and phase purity. Furthermore, the particles are successfully transferred to the aqueous phase using a biocompatible amphiphilic polymer, and demonstrate long-term shelf life. A rigorous characterization protocol ensures that the water-stable MNPs meet all the critical requirements: (1) uniform shape and monodispersity, (2) phase purity, (3) stable magnetic properties approaching that of the bulk, (4) colloidal stability, (5) substantial shelf life and (6) pose no significant in vitro toxicity. Using a dedicated hyperthermia system, we then identified that 16 nm monodisperse MNPs (σ ~ 0.175) respond optimally to our chosen AMF conditions (f = 373 kHz, Ho = 14 kA/m); however, with a broader size distribution (σ ~ 0.284) the Specific Loss Power (SLP) decreases by 30%. Finally, we show that these tailored MNPs demonstrate maximum hyperthermia efficiency by reducing viability of Jurkat cells in vitro, suggesting our optimization translates truthfully to cell populations. In summary, we present a way to intrinsically optimize MFH by tailoring the MNPs to any applied AMF, a required precursor to optimize dose and time of treatment.
doi:10.1002/jbm.a.34011
PMCID: PMC3266447  PMID: 22213652
Magnetic Fluid Hyperthermia; in vitro hyperthermia; monodisperse iron oxide magnetic nanoparticles; cytotoxicity
7.  High Therapeutic Efficiency of Magnetic Hyperthermia in Xenograft Models Achieved with Moderate Temperature Dosages in the Tumor Area 
Pharmaceutical Research  2014;31(12):3274-3288.
ABSTRACT
Purpose
Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.
Methods
Superparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.
Results
Exceptionally high SAR values ranging from 658 ± 53 W*gFe−1 for OD15 up to 900 ± 22 W*gFe−1 for MF66 were determined in an alternating magnetic field (AMF, H = 15.4 kA*m−1 (19 mT), f = 435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4 ± 0.5 nH*m2*kg−1 (OD15) and 8.7 ± 0.2 nH*m2*kg−1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.
Conclusions
Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1417-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s11095-014-1417-0
PMCID: PMC4224751  PMID: 24890197
CEM43T90; in vivo; iron oxide nanoparticles; magnetic hyperthermia; temperature dose
8.  Design Maps for the Hyperthermic Treatment of Tumors with Superparamagnetic Nanoparticles 
PLoS ONE  2013;8(2):e57332.
A plethora of magnetic nanoparticles has been developed and investigated under different alternating magnetic fields (AMF) for the hyperthermic treatment of malignant tissues. Yet, clinical applications of magnetic hyperthermia are sporadic, mostly due to the low energy conversion efficiency of the metallic nanoparticles and the high tissue concentrations required. Here, we study the hyperthermic performance of commercially available formulations of superparamagnetic iron oxide nanoparticles (SPIOs), with core diameter of 5, 7 and 14 nm, in terms of absolute temperature increase ΔT and specific absorption rate (SAR). These nanoparticles are operated under a broad range of AMF conditions, with frequency f varying between 0.2 and 30 MHz; field strength H ranging from 4 to 10 kA m−1; and concentration cMNP varying from 0.02 to 3.5 mg ml−1. At high frequency field (∼30 MHz), non specific heating dominates and ΔT correlates with the electrical conductivity of the medium. At low frequency field (<1 MHz), non specific heating is negligible and the relaxation of the SPIO within the AMF is the sole energy source. We show that the ΔT of the medium grows linearly with cMNP, whereas the SARMNP of the magnetic nanoparticles is independent of cMNP and varies linearly with f and H2. Using a computational model for heat transport in a biological tissue, the minimum requirements for local hyperthermia (Ttissue >42°C) and thermal ablation (Ttissue >50°C) are derived in terms of cMNP, operating AMF conditions and blood perfusion. The resulting maps can be used to rationally design hyperthermic treatments and identifying the proper route of administration – systemic versus intratumor injection – depending on the magnetic and biodistribution properties of the nanoparticles.
doi:10.1371/journal.pone.0057332
PMCID: PMC3581487  PMID: 23451208
9.  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.
doi:10.1117/12.2007673
PMCID: PMC4187246  PMID: 25301993
magnetic nanoparticle; hyperthermia; treatment planning; predictive model; method of auxiliary sources; phantom; eddy currents; cancer therapy; thermal imaging
10.  Simple and Rapid Synthesis of Magnetite/Hydroxyapatite Composites for Hyperthermia Treatments via a Mechanochemical Route 
This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate-substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments.
doi:10.3390/ijms14059365
PMCID: PMC3676787  PMID: 23629669
magnetite; carbonate hydroxyapatite; mechanochemical effect; hyperthermia
11.  Growth Inhibition of Re-Challenge B16 Melanoma Transplant by Conjugates of Melanogenesis Substrate and Magnetite Nanoparticles as the Basis for Developing Melanoma-Targeted Chemo-Thermo-Immunotherapy 
Melanogenesis substrate, N-propionyl-cysteaminylphenol (NPrCAP), is selectively incorporated into melanoma cells and inhibits their growth by producing cytotoxic free radicals. Magnetite nanoparticles also disintegrate cancer cells and generate heat shock protein (HSP) upon exposure to an alternating magnetic field (AMF). This study tested if a chemo-thermo-immunotherapy (CTI therapy) strategy can be developed for better management of melanoma by conjugating NPrCAP on the surface of magnetite nanoparticles (NPrCAP/M). We examined the feasibility of this approach in B16 mouse melanoma and evaluated the impact of exposure temperature, frequency, and interval on the inhibition of re-challenged melanoma growth. The therapeutic protocol against the primary transplanted tumor with or without AMF exposure once a day every other day for a total of three treatments not only inhibited the growth of the primary transplant but also prevented the growth of the secondary, re-challenge transplant. The heat-generated therapeutic effect was more significant at a temperature of 43°C than either 41°C or 46°C. NPrCAP/M with AMF exposure, instead of control magnetite alone or without AMF exposure, resulted in the most significant growth inhibition of the re-challenge tumor and increased the life span of the mice. HSP70 production was greatest at 43°C compared to that with 41°C or 46°C. CD8+T cells were infiltrated at the site of the re-challenge melanoma transplant.
doi:10.1155/2009/457936
PMCID: PMC2760320  PMID: 19830247
12.  Kinetics and pathogenesis of intracellular magnetic nanoparticle cytotoxicity 
Proceedings of SPIE  2011;7901:10.1117/12.876519.
Magnetic nanoparticles excited by alternating magnetic fields (AMF) have demonstrated effective tumor-specific hyperthermia. This treatment is effective as a monotherapy as well as a therapeutic adjuvant to chemotherapy and radiation. Iron oxide nanoparticles have been shown, so far, to be non-toxic, as are the exciting AMF fields when used at moderate levels. Although higher levels of AMF can be more effective, depending on the type of iron oxide nanoparticles use, these higher field strengths and/or frequencies can induce normal tissue heating and toxicity. Thus, the use of nanoparticles exhibiting significant heating at low AMF strengths and frequencies is desirable. Our preliminary experiments have shown that the aggregation of magnetic nanoparticles within tumor cells improves their heating effect and cytotoxicity per nanoparticle. We have used transmission electron microscopy to track the endocytosis of nanoparticles into tumor cells (both breast adenocarcinoma (MTG-B) and acute monocytic leukemia (THP-1) cells). Our preliminary results suggest that nanoparticles internalized into tumor cells demonstrate greater cytotoxicity when excited with AMF than an equivalent heat dose from excited external nanoparticles or cells exposed to a hot water bath. We have also demonstrated that this increase in SAR caused by aggregation improves the cytotoxicity of nanoparticle hyperthermia therapy in vitro.
doi:10.1117/12.876519
PMCID: PMC3874720  PMID: 24382988
Hyperthermia; nanoparticle; AMF; SAR; specific absorption rate; tumor; intracellular hyperthermia
13.  Block Copolymer Cross-linked Nanoassemblies Improve Particle Stability and Biocompatibility of Superparamagnetic Iron Oxide Nanoparticles 
Pharmaceutical research  2012;30(2):552-561.
Purpose
To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs).
Methods
Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe3O4 IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe3O4 IONPs (Citrate-IONPs).
Results
CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43 °C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (> 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40 ~ 42 °C) with an alternating magnetic field (AMF).
Conclusion
Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications.
doi:10.1007/s11095-012-0900-8
PMCID: PMC4076800  PMID: 23080062
Nanoparticles; superparamagnetic iron oxide; cross-linked nanoassemblies; magnetic resonance imaging; hyperthermia
14.  Local hyperthermia for esophageal cancer in a rabbit tumor model: Magnetic stent hyperthermia versus magnetic fluid hyperthermia 
Oncology Letters  2013;6(6):1550-1558.
Magnetic-mediated hyperthermia (MMH) is a promising local thermotherapy approach for cancer treatment. The present study investigated the feasibility and effectiveness of MMH in esophageal cancer using a rabbit tumor model. The therapeutic effect of two hyperthermia approaches, magnetic stent hyperthermia (MSH), in which heat is induced by the clinical stent that is placed inside the esophagus, and magnetic fluid hyperthermia (MFH), where magnetic nanoparticles are applied as the agent, was systematically evaluated. A rabbit esophageal tumor model was established by injecting VX2 carcinoma cells into the esophageal submucosa. The esophageal stent was deployed perorally into the tumor segment of the esophagus. For the MFH, magnetic nanoparticles (MNPs) were administered to the rabbits by intratumoral injection. The rabbits were exposed under a benchtop applicator using an alternative magnetic field (AMF) with 300 kHz frequency for the hyperthermia treatment. The results demonstrated that esophageal stents and MNPs had ideal inductive heating properties upon exposure under an AMF of 300 kHz. MSH, using a thermal dose of 46°C with a 10-min treatment time, demonstrated antitumor effects on the rabbit esophageal cancer. However, the rabbit esophageal wall is not heat-resistant. Therefore, a higher temperature or longer treatment time may lead to necrosis of the rabbit esophagus. MFH has a significant antitumor effect by confining the heat within the tumor site without damaging the adjacent normal tissues. The present study indicates that the two hyperthermia procedures have therapeutic effects on esophageal cancer, and that MFH may be more specific than MSH in terms of temperature control during the treatment.
doi:10.3892/ol.2013.1618
PMCID: PMC3833863  PMID: 24260045
magnetic mediated hyperthermia; esophageal cancer; magnetic nanoparticles; esophageal stent; alternative magnetic field
15.  Method to reduce non-specific tissue heating of small animals in solenoid coils 
Purpose
Solenoid coils that generate time-varying or alternating magnetic fields (AMFs) are used in biomedical devices for research, imaging and therapy. Interactions of AMF and tissue produce eddy currents that deposit power within tissue, thus limiting effectiveness and safety. We aim to develop methods that minimise excess heating of mice exposed to AMFs for cancer therapy experiments.
Materials and methods
Numerical and experimental data were obtained to characterise thermal management properties of water using a continuous, custom water jacket in a four-turn simple solenoid. Theoretical data were obtained with method-of-moments (MoM) numerical field calculations and finite element method (FEM) thermal simulations. Experimental data were obtained from gel phantoms and mice exposed to AMFs having amplitude >50kA/m and frequency of 160 kHz.
Results
Water has a high specific heat and thermal conductivity, is diamagnetic, polar, and nearly transparent to magnetic fields. We report at least a two-fold reduction of temperature increase from gel phantom and animal models when a continuous layer of circulating water was placed between the sample and solenoid, compared with no water. Thermal simulations indicate the superior efficiency in thermal management by the developed continuous single chamber cooling system over a double chamber non-continuous system. Further reductions of heating were obtained by regulating water temperature and flow for active cooling.
Conclusions
These results demonstrate the potential value of a contiguous layer of circulating water to permit sustained exposure to high intensity alternating magnetic fields at this frequency for research using small animal models exposed to AMFs.
doi:10.3109/02656736.2013.764023
PMCID: PMC3991111  PMID: 23402327
magnetic induction; solenoid coil; hyperthermia; thermal therapy; water
16.  Local Hyperthermia Enhances Thrombosis in Aneurysms Containing Platinum Coils 
Interventional Neuroradiology  2005;10(3):203-211.
Summary
Despite recent technical advances in embolization of cerebral aneurysms with platinum coils, some aneurysms eventually resulted in incomplete packing with remnant neck or dome filling. Such a situation with a remaining inflow zone may pose a risk of rupture and subsequent regrowth. Metals characteristically generate heat under high-frequency alternating magnetic fields (AMF). We used this property to induce local hyperthermia and promote thrombogenesis in incompletely packed aneurysms.
Glass model aneurysms packed with coils were subjected to AMF to investigate the correlation between weight of platinum and temperature elevation and the correlation between flow rates of water through the model and temperature elevation. Next, activated coagulation time (ACT) of blood obtained from dogs was studied at various temperatures. Finally, side-wall aneurysms created in the canine carotid artery using a venous patch were packed with platinum coils. Change in temperature and angiographic changes were investigated after AMF application.
In the glass model, the weight of platinum was correlated with elevation of temperature, and a negative logarithmic correlation was evident between flow rate and elevation of temperature. Elevation of blood sample temperature tended to shorten ACT. In canine carotid aneurysms, elevation of intra-aneurysmal temperature was confirmed and sufficient elevation of temperature was found to promote angiographically evident thrombogenesis of the remnant space after AMF application.
Local hyperthermia may be useful in completing luminal obliteration of aneurysms after coil embolization. It may particularly useful for ruptured aneurysms to prevent the early rerupture.
PMCID: PMC3463249  PMID: 20587232
hyperthermia, cerebral aneurysm, coil embolization
17.  Preliminary study of injury from heating systemically delivered, nontargeted dextran–superparamagnetic iron oxide nanoparticles in mice 
Nanomedicine (London, England)  2012;7(11):1697-1711.
Aim
To assess the potential for injury to normal tissues in mice due to heating systemically delivered magnetic nanoparticles in an alternating magnetic field (AMF).
Materials & methods
Twenty three male nude mice received intravenous injections of dextran–superparamagnetic iron oxide nanoparticles on days 1–3. On day 6, they were exposed to AMF. On day 7, blood, liver and spleen were harvested and analyzed.
Results
Iron deposits were detected in the liver and spleen. Mice that had received a high-particle dose and a high AMF experienced increased mortality, elevated liver enzymes and significant liver and spleen necrosis. Mice treated with low-dose superparamagnetic iron oxide nanoparticles and a low AMF survived, but had elevated enzyme levels and local necrosis in the spleen.
Conclusion
Magnetic nanoparticles producing only modest heat output can cause damage, and even death, when sequestered in sufficient concentrations. Dextran–superparamagnetic iron oxide nanoparticles are deposited in the liver and spleen, making these the sites of potential toxicity.
doi:10.2217/nnm.12.65
PMCID: PMC3991127  PMID: 22830502
hyperthermia; liver; magnetic nanoparticle; SPIO; spleen; toxicity
18.  Magnetic Nanoparticles from Magnetospirillum gryphiswaldense Increase the Efficacy of Thermotherapy in a Model of Colon Carcinoma 
PLoS ONE  2014;9(10):e108959.
Magnetic nanoparticles (MNPs) are capable of generate heating power under the influence of alternating magnetic fields (AMF); this behaviour recently opened new scenarios for advanced biomedical applications, mainly as new promising tumor therapies. In this paper we have tested magnetic nanoparticles called magnetosomes (MNs): a class of MNPs naturally produced by magnetotactic bacteria. We extracted MNs from Magnetospirillum gryphiswaldense strain MSR-1 and tested the interaction with cellular elements and anti-neoplastic activity both in vitro and in vivo, with the aim of developing new therapeutic approaches for neoplastic diseases. In vitro experiments performed on Human Colon Carcinoma HT-29 cell cultures demonstrated a strong uptake of MNs with no evident signs of cytotoxicity and revealed three phases in the interaction: adherence, transport and accumulation in Golgi vesicles. In vivo studies were performed on subcutaneous tumors in mice; in this model MNs are administered by direct injection in the tumor volume, then a protocol consisting of three exposures to an AMF rated at 187 kHz and 23kA/m is carried out on alternate days, over a week. Tumors were monitored by Magnetic Resonance Imaging (MRI) to obtain information about MNs distribution and possible tissue modifications induced by hyperthermia. Histological analysis showed fibrous and necrotic areas close to MNs injection sites in mice subjected to a complete thermotherapy protocol. These results, although concerning a specific tumor model, could be useful to further investigate the feasibility and efficacy of protocols based on MFH. Magnetic nanoparticles naturally produced and extracted from bacteria seem to be promising candidates for theranostic applications in cancer therapy.
doi:10.1371/journal.pone.0108959
PMCID: PMC4188607  PMID: 25289664
19.  Comparison of iron oxide nanoparticle and microwave hyperthermia alone or combined with cisplatinum in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876535.
Surgery, radiation and chemotherapy are currently the most commonly used cancer therapies. Hyperthermia has been shown to work effectively with radiation and chemotherapy cancer treatments. The major obstacle faced by previous hyperthermia techniques has been the inability to deliver heat to the tumor in a precise manner. The ability to deliver cytotoxic hyperthermia to tumors (from within individual cells) via iron oxide magnetic nanoparticles (mNP) is a promising new technology that has the ability to greatly improve the therapeutic ratio of hyperthermia as an individual modality and as an adjuvant therapy in combination with other modalities. Although the parameters have yet to be conclusively defined, preliminary data suggests mNP hyperthermia can achieve greater cytotoxicity (in vitro) than conventional water bath hyperthermia methods. At this time, our theory is that intracellular nanoparticle heating is more effective in achieving the combined effect than extracellular heating techniques.1 However, understanding the importance of mNP association and uptake is critical in understanding the potential novelty of the heating modality. Our preliminary data suggests that the mNP heating technique, which did not provide time for particle uptake by the cells, resulted in similar efficacy to microwave hyperthermia. mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses
Methods
One hour before nanoparticle hyperthermia, CDDP chemotherapy (5mg/kg of body mass) was delivered intraperitoneally (IP). Iron oxide nanoparticles, 7.5mg of iron per gram of tumor, were injected into MTGB flank tumors in female C3H mice immediately before activation. A 170 KHz, 400-450 Oe alternating magnetic field (AMF) was used to induce particle heating. A comparison of nanoparticle induced hyperthermia to non-nanoparticle induced hyperthermia was also made using a 915 MHz microwave generator. Treatment duration was determined by the use of the cumulative equivalent minutes (CEM) algorithm. A CEM 60 was selected as the thermal dose for all experimental groups.
Results
1) Preliminary mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses.
2) mNP hyperthermia delivered 10 minutes post mNP injection and microwave hyperthermia, with the same thermal dose, demonstrate similar treatment efficacy.
doi:10.1117/12.876535
PMCID: PMC3877302  PMID: 24386533
Iron oxide; nanoparticle; hyperthermia; microwave; AMF; chemotherapy; cisplatinum; MTGB
20.  Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment 
Gliomas are a group of heterogeneous primary central nervous system (CNS) tumors arising from the glial cells. Malignant gliomas account for a majority of malignant primary CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent and malignant glioma, and despite the recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetic hyperthermia (MHT), which consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field (AMF), has shown positive results in both preclinical and clinical assays. The aim of this review is to assess the relevance of hyperthermia induced by magnetic nanoparticles in the treatment of gliomas and to note the possible variations of the technique and its implication on the effectiveness of the treatment. We performed an electronic search in the literature from January 1990 to October 2010, in various databases, and after application of the inclusion criteria we obtained a total of 15 articles. In vitro studies and studies using animal models showed that MHT was effective in the promotion of tumor cell death and reduction of tumor mass or increase in survival. Two clinical studies showed that MHT could be applied safely and with few side effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by MHT. Based on these data, we could conclude that MHT proved to be efficient in most of the experiments, and that the improvement of the nanocomposites as well as the AMF equipment might contribute toward establishing MHT as a promising tool in the treatment of malignant gliomas.
doi:10.2147/IJN.S14737
PMCID: PMC3107718  PMID: 21674016
brain tumor; magnetic hyperthermia; magnetic nanoparticle
21.  Iron oxide nanoparticle hyperthermia and chemotherapy cancer treatment 
The benefit of combining hyperthermia and chemotherapy to treat cancer is well established. However, combined therapy has not yet achieved standard of care status. The reasons are numerous and varied, however the lack of significantly greater tumor cell sensitivity to heat (as compared to normal cells) and the inability to deliver heat to the tumor in a precise manner have been major factors. Iron oxide nanoparticle (IONP) hyperthermia, alone and combined with other modalities, offers a new direction in hyperthermia cancer therapy via improved tumor targeting and an improved therapeutic ratio. Our preliminary studies have demonstrated tumor cell cytotoxicity (in vitro and in vivo) with IONP heat and cisplatinum (CDDP) doses lower than those necessary when using conventional heating techniques or cisplatinum alone. Ongoing studies suggest such treatment could be further improved through the use of targeted nanoparticles.
Methods
In vivo: IONPs (5mg of iron per gram of tumor) were administered into MTG-B flank tumors in female C3H-HEJ mice directly after cisplatinum chemotherapy (0.1ml/kg of body mass) was intraperitoneally injected. An 160 KHz, 350–450 Oe AMF (alternating magnetic field) was used to induce particle heating.
In vitro: Mouse mammary adenocarcinoma cells (MTG-B) cells were grown and exposed to IONP hyperthermia and cisplatinum. IONPs not associated with cells were removed by washing prior to heat induction by an AMF field. Acute cell survival, via trypan blue assay, was used to quantify the level of cytotoxicity.
Results
In vitro studies, using IONP + cisplatinum, have demonstrated promising cytotoxicity enhancement. Ongoing studies are being pursued to further define the mechanism of action, temporal associations and pathophysiology of combined IONP hyperthermia and chemotherapy treatment. Preliminary in vivo IONP /cisplatinum studies have shown a tumor growth delay/volume reduction greater than either modality alone at comparable doses. Further enhancement of this treatment success appears to depend on a better understanding of IONP dose and tumor cell association, chemotherapy dose and administration technique, the spatial and temporal treatment relationship of the two modalities and optimal AMF - IONP coupling.
doi:10.1117/12.810024
PMCID: PMC4208066  PMID: 25346581
Iron oxide; nanoparticle; AMF; chemotherapy; cisplatinum; murine; MTG-B; HT-29
22.  The influence of colloidal parameters on the specific power absorption of PAA-coated magnetite nanoparticles 
Nanoscale Research Letters  2011;6(1):383.
The suitability of magnetic nanoparticles (MNPs) to act as heat nano-sources by application of an alternating magnetic field has recently been studied due to their promising applications in biomedicine. The understanding of the magnetic relaxation mechanism in biocompatible nanoparticle systems is crucial in order to optimize the magnetic properties and maximize the specific absorption rate (SAR). With this aim, the SAR of magnetic dispersions containing superparamagnetic magnetite nanoparticles bio-coated with polyacrylic acid of an average particle size of ≈10 nm has been evaluated separately by changing colloidal parameters such as the MNP concentration and the viscosity of the solvent. A remarkable decrease of the SAR values with increasing particle concentration and solvent viscosity was found. These behaviours have been discussed on the basis of the magnetic relaxation mechanisms involved.
PACS: 80; 87; 87.85jf
doi:10.1186/1556-276X-6-383
PMCID: PMC3211476  PMID: 21711915
23.  Modified Solenoid Coil That Efficiently Produces High Amplitude AC Magnetic Fields With Enhanced Uniformity for Biomedical Applications 
IEEE transactions on magnetics  2012;48(1):47-52.
In this paper, we describe a modified solenoid coil that efficiently generates high amplitude alternating magnetic fields (AMF) having field uniformity (≤10%) within a 125-cm3 volume of interest. Two-dimensional finite element analysis (2D-FEA) was used to design a coil generating a targeted peak AMF amplitude along the coil axis of ~100 kA/m (peak-to-peak) at a frequency of 150 kHz while maintaining field uniformity to >90% of peak for a specified volume. This field uniformity was realized by forming the turns from cylindrical sections of copper plate and by adding flux concentrating rings to both ends of the coil. Following construction, the field profile along the axes of the coil was measured. An axial peak field value of 95.8 ± 0.4 kA/m was measured with 650 V applied to the coil and was consistent with the calculated results. The region of axial field uniformity, defined as the distance over which field ≥90% of peak, was also consistent with the simulated results. We describe the utility of such a device for calorimetric measurement of nanoparticle heating for cancer therapy and for magnetic fluid hyperthermia in small animal models of human cancer.
doi:10.1109/TMAG.2011.2162527
PMCID: PMC4226412  PMID: 25392562
AC magnetic fields; high-amplitude; solenoid; uniformity
24.  FEM numerical model study of heating in magnetic nanoparticles 
Proceedings of SPIE  2011;7901:10.1117/12.875288.
Electromagnetic heating of nanoparticles is complicated by the extremely short thermal relaxation time constants and difficulty of coupling sufficient power into the particles to achieve desired temperatures. Magnetic field heating by the hysteresis loop mechanism at frequencies between about 100 and 300 kHz has proven to be an effective mechanism in magnetic nanoparticles. Experiments at 2.45 GHz show that Fe3O4 magnetite nanoparticle dispersions in the range of 1012 to 1013 NP/mL also heat substantially at this frequency.
An FEM numerical model study was undertaken to estimate the order of magnitude of volume power density, Qgen (W m−3) required to achieve significant heating in evenly dispersed and aggregated clusters of nanoparticles. The FEM models were computed using Comsol Multiphysics; consequently the models were confined to continuum formulations and did not include film nano-dimension heat transfer effects at the nanoparticle surface. As an example, the models indicate that for a single 36 nm diameter particle at an equivalent dispersion of 1013 NP/mL located within one control volume (1.0 × 10−19 m3) of a capillary vessel a power density in the neighborhood of 1017 (W m−3) is required to achieve a steady state particle temperature of 52 °C — the total power coupled to the particle is 2.44 μW. As a uniformly distributed particle cluster moves farther from the capillary the required power density decreases markedly. Finally, the tendency for particles in vivo to cluster together at separation distances much less than those of the uniform distribution further reduces the required power density.
doi:10.1117/12.875288
PMCID: PMC3877304  PMID: 24386534
FEM numerical models; Nanoparticle heating; Ferromagnetic nanoparticles
25.  Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer 
Proceedings of SPIE  2013;8584:1656985-.
Background
Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model.
Methods
The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target.
Results
The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder ≥1°C/min to a steady-state of 42°C.
Conclusion
Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.
doi:10.1117/12.2005623
PMCID: PMC3702184  PMID: 23837123
Bladder cancer; Hyperthermia; iron oxide; magnetite; nanoparticle heating; thermal dosimetry

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