The activation of magnetic nanoparticles (mNPs) by an alternating magnetic field (AMF) is currently being explored as technique for targeted therapeutic heating of tumors. Various types of superparamagnetic and ferromagnetic particles, with different coatings and targeting agents, allow for tumor site and type specificity. Magnetic nanoparticle hyperthermia is also being studied as an adjuvant to conventional chemotherapy and radiation therapy. This review provides an introduction to some of the relevant biology and materials science involved in the technical development and current and future use of mNP hyperthermia as clinical cancer therapy.

Purpose The purpose of this study was to examine the therapeutic effect of magnetic nanoparticle hyperthermia (mNPH) combined with systemic cisplatin chemotherapy in a murine mammary adenocarcinoma model (MTGB). Materials and methods An alternating magnetic field (35.8 kA/m at 165 kHz) was used to activate 110 nm hydroxyethyl starch-coated magnetic nanoparticles (mNP) to a thermal dose of 60 min at 43 °C. Intratumoral mNP were delivered at 7.5 mg of Fe/cm3 of tumour (four equal tumour quadrants). Intraperitoneal cisplatin at 5 mg/kg body weight was administered 1 h prior to mNPH. Tumour regrowth delay time was used to assess the treatment efficacy. Results mNP hyperthermia, combined with cisplatin, was 1.7 times more effective than mNP hyperthermia alone and 1.4 times more effective than cisplatin alone (p<0.05). Conclusions Our results demonstrate that mNP hyperthermia can result in a safe and significant therapeutic enhancement for cisplatin cancer therapy.

Nanoparticle-based therapies are currently being explored for both the imaging and treatment of primary and metastatic cancers. Effective nanoparticle cancer therapy requires significant accumulations of nanoparticles within the tumor environment. Various techniques have been used to improve tumor nanoparticle uptake and biodistribution. Most notable of these techniques are the use of tumor-specific-peptide-conjugated nanoparticles and chemical modification of the nanoparticles with immune-evading polymers. Another strategy for improving the tumor uptake of the nanoparticles is modification of the tumor microenvironment with a goal of enhancing the enhanced permeability and retention effect inherent to solid tumors. We demonstrate a two-fold increase in the tumor accumulation of systemically delivered iron oxide nanoparticles following a single, 15 Gy radiation dose in a syngeneic mouse breast tumor model. This increase in nanoparticle tumor accumulation correlates with a radiation-induced decrease in tumor interstitial pressure and a subsequent increase in vascular permeability. Keywords ionizing radiation; nanoparticle; tumor; biodistribution; interstitial pressure BackgroundA variety of hyperthermia-based techniques[1], including intratumoral magnetic nanoparticle (mNP) hyperthermia [2], have been used to treat tumors. The difference in mNP hyperthermia, as compared to conventional hyperthermia, is the ability tofocally heat according to mNP uptake and biodistribution in both primary and metastatic tumors. One of the most significant challenges is delivering an effective concentration ofnanoparticles to tumor cells. Investigators have relied on increasing nanoparticle circulation time through evasion of the reticuloendothelial system (RES) [2] by modifying nanoparticle surface © 2012 Elsevier Inc. All rights reserved. * author(s) to whom correspondence should be addressed: andrew.j.giustini.th@dartmouth.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Financial and competing interests disclosure: The authors report no conflicts of interest. NIH Public Access Materials Methods Cell CultureMTG-B mouse mammary adenocarcinoma cells were cultured in 150 cm 2 cell culture flasks (Corning Inc., Lowell, MA) in Alpha MEM medium (10% fetal bovine serum, 1% penicillin-streptomycin, 1% L-glutamine; all from Thermo Fisher Scientific Inc., Waltham, MA., USA). Cells were then trypsinized (0.25% trypsin in EDTA, Mediatech, Inc., Manassas, Va) and resuspended in serum-free Alpha MEM at 10 7 cells/ml. Murine tumor modelOne hundred μL (10 6 cells) was implanted bilaterally in ...

Magnetic nanoparticle hyperthermia therapy is a promising technology for cancer treatment. The technique involves delivering magnetic nanoparticles (MNPs) into tumors, then activating the MNPs using an alternating magnetic field (AMF). The AMF generating system produces not only a magnetic field, but also an electric field. The electric field penetrates normal tissue and induces eddy currents, which result in unwanted heating of normal tissues. The 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 limitation has posed a nontrivial challenge for researchers who have attempted to scale up from a small animal model to clinically relevant volumes of tissue. For example, the efficacy limiting nature of eddy current heating has been observed in a recent clinical trial, where patient discomfort was reported. Until now, much of the literature regarding increasing the efficacy of MNP hyperthermia therapy has focused on increasing MNP specific absorption rate or increasing the concentration of MNPs in the tumor; i.e. - improving efficacy at what is thought to be the maximum safe field strength and frequency. There has been a relative dearth of studies focused on decreasing the maximum temperature resulting from eddy current heating, to increase therapeutic ratio. This paper presents two simple and 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 to leverage these insights for the mitigation of eddy current heating during MNP hyperthermia therapy. Phantom studies show that these techniques, termed the displacement and motion techniques, reduce maximum temperature due to eddy currents by 74% and 19% in simulation, and by 77% and 33% experimentally. Further study is required to optimize 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.

Iron oxide nanoparticles present a promising alternative to conventional energy deposition-based tissue therapies. The success of such nanoparticles as a therapeutic for diseases like cancer, however, depends heavily on the particles’ ability to localize to tumor tissue as well as provide minimal toxicity to surrounding tissues and key organs such as those involved in the reticuloendothelial system (RES). We present here the results of a long term clearance study where mice injected intravenously with 2 mg Fe of 100 nm dextran-coated iron oxide nanoparticles were sacrificed at 14 and 580 days post injection. Histological analysis showed accumulation of the nanoparticles in some RES organs by the 14 day time point and clearance of the nanoparticles by the 580 day time point with no obvious toxicity to organs. An additional study reported herein employs 20 nm and 110 nm starch-coated iron oxide nanoparticles at 80 mg Fe/kg mouse in a size/biodistribution study with endpoints at 4, 24 and 72 hours. Preliminary results show nanoparticle accumulation in the liver and spleen with some elevated iron accumulation in tumoral tissues with differences between the 20 nm and the 110 nm nanoparticle depositions.

Purpose The purpose of this study was to compare the efficacy of iron oxide/magnetic nanoparticle hyperthermia (mNPH) and 915 MHz microwave hyperthermia at the same thermal dose in mouse mammary adenocarcinoma model. Materials and Methods A thermal dose equivalent to 60 minutes at 43°C (CEM 60) was delivered to a syngeneic mouse mammary adenocarcinoma flank tumor (MTGB) via mNPH or locally delivered 915 MHz microwaves. mNPH was generated with ferromagnetic, hydroxyethyl starch coated magnetic nanoparticles. Following mNP delivery, the mouse/tumor was exposed to an alternating magnetic field (AMF). The microwave hyperthermia treatment was delivered by a 915 MHz microwave surface applicator. Time required for the tumor to reach three times the treatment volume was used as the primary study endpoint. Acute pathological effects of the treatments were determined using conventional histopathological techniques. Results Locally delivered mNPH resulted in a modest improvement in treatment efficacy as compared to microwave hyperthermia (p=0.09) when prescribed to the same thermal dose. Tumors treated with mNPH also demonstrated reduced peritumoral normal tissue damage. Conclusions Our results demonstrate similar tumor treatment efficacy when tumor heating is delivered by locally delivered mNPs and 915 MHz microwaves at the same measured thermal dose. However, mNPH treatments did not result in the same type or level of peritumoral damage seen with the microwave hyperthermia treatments. These data suggest that mNP hyperthermia is capable of improving the therapeutic ratio for locally delivered tumor hyperthermia. These results further indicate that this improvement is due to improved heat localization in the tumor.

It has recently been shown that cancer treatments such as radiation and hyperthermia, which have conventionally been viewed to have modest immune based anti-cancer effects, may, if used appropriately stimulate a significant and potentially effective local and systemic anti-cancer immune effect (abscopal effect) and improved prognosis. Using eight spontaneous canine cancers (2 oral melanoma, 3 oral amelioblastomas and 1 carcinomas), we have shown that hypofractionated radiation (6 x 6 Gy) and/or magnetic nanoparticle hyperthermia (2 X 43°C / 45 minutes) and/or an immunogenic virus-like nanoparticle (VLP, 2 x 200 μg) are capable of delivering a highly effective cancer treatment that includes an immunogenic component. Two tumors received all three therapeutic modalities, one tumor received radiation and hyperthermia, two tumors received radiation and VLP, and three tumors received only mNP hyperthermia. The treatment regimen is conducted over a 14-day period. All patients tolerated the treatments without complication and have had local and distant tumor responses that significantly exceed responses observed following conventional therapy (surgery and/or radiation). The results suggest that both hypofractionated radiation and hyperthermia have effective immune responses that are enhanced by the intratumoral VLP treatment. Molecular data from these tumors suggest Heat Shock Protein (HSP) 70/90, calreticulin and CD47 are targets that can be exploited to enhance the local and systemic (abscopal effect) immune potential of radiation and hyperthermia cancer treatment.

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.