Size dependent heat generation of magnetite nanoparticles under AC magnetic field for cancer therapy
© Motoyama et al; licensee BioMed Central Ltd. 2008
Received: 16 April 2008
Accepted: 20 October 2008
Published: 20 October 2008
We have developed magnetic cationic liposomes (MCLs) that contained magnetic nanoparticles as heating mediator for applying them to local hyperthermia. The heating performance of the MCLs is significantly affected by the property of the incorporated magnetite nanoparticles. We estimated heating capacity of magnetite nanoparticles by measuring its specific absorption rate (SAR) against irradiation of the alternating magnetic field (AMF).
Magnetite nanoparticles which have various specific-surface-area (SSA) are dispersed in the sample tubes, subjected to various AMF and studied SAR.
Heat generation of magnetite particles under variable AMF conditions was summarized by the SSA. There were two maximum SAR values locally between 12 m2/g to 190 m2/g of the SSA in all ranges of applied AMF frequency and those values increased followed by the intensity of AMF power. One of the maximum values was observed at approximately 90 m2/g of the SSA particles and the other was observed at approximately 120 m2/g of the SSA particles. A boundary value of the SAR for heat generation was observed around 110 m2/g of SSA particles and the effects of the AMF power were different on both hand. Smaller SSA particles showed strong correlation of the SAR value to the intensity of the AMF power though larger SSA particles showed weaker correlation.
Those results suggest that two maximum SAR value stand for the heating mechanism of magnetite nanoparticles represented by hysteresis loss and relaxation loss.
Hyperthermic cancer treatments have been used for many years, particularly in anticancer therapy . However, efficiency of the treatment did not satisfy in the clinical scene, because of its difficulty of raising the objective tissue temperature properly . There Magnetic Fluid Hyperthermia (MFH), by using the magnetite (Fe3O4) as a preferable heating source, due to its strong magnetic property and low toxicity, is a promising approach for treating cancer . MFH can raise the temperature in the tumor locally up to 41–46°C if magnetic fluid was selectively introduced and therefore kill tumor cells directory without damages of ambient healthy cells. In this technique, magnetite particles that have ferromagnetic or superparamagnetic property are dispersed into the aqueous phase and introduced into tumor cells. In our previous study, magnetite nanopaticles covered with the cationic liposome (magnetite cationic liposomes, MCLs) to show higher adhesion properties to the cell surfaces that is charged negatively [4–6]. In previous animal studies, we have demonstrated the efficacy of hyperthermia induce using MCLs in several types of tumor model; for instance, B16 melanoma in mice [7, 8], T9 glioma in rats [6, 9], osteosarcoma in hamsters , prostate cancer in mice  and MM46 mouse mammary carcinoma . magnetite cationic liposomes (MCLs) Introduced magnetite particles transform the energy of the AC magnetic field into heat by several physical mechanisms, and its efficacy strongly depends on the frequency of the outer field as well as the particle's magnetic properties correlated to its diameter [3, 13].
In our present study, we drew attention to the specific-surface area (SSA) as an represented mediator for expressing particle size and microscopic structure. The SARs of those magnetic particles were studied under several conditions of AC magnetic field or strength of the power and the frequency were changed. Here, SAR is defined as the energy amount converted into heat per unit time and unit mass.
Physical properties of the magnetite particles for the experiments
TEM method (nm)
Saturated magnetization (Am2/kg)
Coercivity (k A/m)
Kappa-carrageenan and magnesium chloride were purchased from Wako chemicals (Osaka, Japan).
Preparation of the heating samples
Magnetite nanopartiles were dispersed in distilled water with the same concentration of 20 mg/ml and treated with ultrasound sonication for 30 minutes. Those magnetite dispersions were filled in the cylindrical polypropylene tubes that has 15 mm inner diameter with the kappa-carrageenan and the dispersions were gelated by appropriated dose of magnesium chloride. Temperature increase was caused by the upwardly generated AC magnetic field from the surface of the irradiation coil of the AMF radiator. As a whole, 2 g of the samples that contained 5 mg of magnetite nanoparticles were put in the sample tubes. As an control, the kappa-carrageenan solution was put into the sample tube without magnetite dispersions, and gelated by magnesium chloride.
Variation of the frequency and the electrical power for AMF irradiator
Applied power (kW)
1.6, 3.5, 5.2
2.5, 6.0, 13.0
2.5, 6.0, 13.1
The temperature of the samples were measured by using optical thermometer (FX-9020; Anritsu Meter Co., Tokyo). After the experiments, all samples were dissolved by adding 12N hydrochloric acid and diluted to measure the iron contents by the potassium thiocyanate method .
Cnsequently we determined the magnetite concentration in the sample tubes precisely. The control was also exposed under the AMF, and confirmed that has no affection to heat generation. The SAR values of the samples were determined from the time dependent calorimetric measurements.
Physical and magnetic properties of 13 magnetic nanoparticle samples
In the present study, 13 magnetic nanoparticles that are various diameters of the same materials Fe3O4 were precisely prepared by the same way. As shown in Table 1, magnetite average diameters measured by DLS method were almost ten times larger than that of the primary particles measured by TEM method. We considered that some kind of the aggregations of the primary particles occurred. Both average diameters seem to correlate well with each other. However, extremely large SSA was obtained even in the similar DLS diameter, i.e. 74 m2/g of SSA in sample D and 190 m2/g of SSA in sample M.
Saturated magnetization and coercivity were also measured as magnetic properties. These magnetic properties were not correlated with DLS diameter. However, it was found that saturated magnetization was strongly correlated with SSA.
Temperature profiles by AC magnetic field irradiation
Effects of SSA of the particles on SAR value.
In the present study, 13 magnetic nanoparticles that are various diameters of the same materials Fe3O4 were precisely prepared by the same way and SAR was measured under various AC frequency and AC power. Such summarized data have been firstly reported by us in the present paper. To the best of our knowledge, it was firstly found that SSA is better index for SAR.
From polydespersity index of DLS listed in Table 1 and TEM photographs, it was found that there was not any particle with extremely wide size distribution. Therefore, it is considerable that there are different degree of aggregates and different packing density of aggregate, because large SSA was obtained even in samples with similar DLS diameter. It is considerable that samples with high packing density behave as a multidomain particle and higher saturated magnetization was obtained.
In Fig. 4, we showed the SARs of the magnetite particles which were measured under variable AMF conditions. There were two local maximum values of the SAR observed when the SARs were plotted against to the SSAs, which were approximately 90 m2/g (a) and 120 m2/g (b) separately in all the experimental intensities of AC magnetic fields.
It has been reported that the SAR of magnetite particles in an external AC magnetic field can be attributed to two kinds of power loss mechanisms; one is hysteresis loss and others is relaxation loss [16–18]. The grade of these two power losses depends on the particle sizes. The heating due to hysteresis losses are caused by magnetic domain wall displacements under an AC magnetic field. Therefore, it has been reported that the hysteresis loss induced heating needs larger size of magnetic multidomain particles. On the other hand, heating induced by relaxation loss under an AC magnetic field occur to smaller particles that has not domain wall and consists of the single domain structure .
The SAR values for the particles below the dividing line which exist around 110 m2/g of SSA seemed more susceptible against to the power of AC magnetic field in all frequencies as well. As shown in Fig. 5, it was found that heat generation by two processes was found against SSA. It is strongly suggested that these are happened by clearly different mechanism for heat generation. It is likely that those are relaxation loss and hysteresis loss, respectively, although we could not mention the reason why local maximum is 120 m2/g and that was not the smallest SSA in the particles. More profound discussion might be revealed by further experiment. From Table 1, it was found that saturated magnetization was strongly correlated with SSA. In the hysteresis loss, SAR is defined by the area of hysteresis curve. This might be one of the reasons why SSA is better index for SAR, although the reason why saturated magnetization is correlated with SSA still remains to be elucidated.
Since the heating mechanism of the magnetite nanoparticles of different SSA have different attributions from the intensity of AMF, it is considerably needed to optimize the particle SSA for the treatment of MFH. As shown in Fig. 5, the diagram of SAR of the sample K, which has larger SSA, was maintained virtually constant against to the power of AMF in all range of its frequency (Slopes are closed to 0). Therefore for the MFH treatment, when the magnetite particles those have more than 110 m2/g of SSA and less than 10 nm of particle diameter are used as the heating mediator, we expect the stable supply of heat could be performed imperviously to the power of AMF.
Comparably, smaller SSA particles generates heat linearly against the strength of the AMF (Slopes in Table 3 are large). That is to say, smaller SSA particles seem to be suited for treating various region of the body part for the MFH treatment because the SAR curve for the smaller SSA particles are adjustable and easily increased linearly by manipulating the power of AMF. In addition the dose of the smaller SSA particles possibly could be hold down when the high-power of AMF are applicable for treatment. It would be also able to heat deep portion of the body part sufficiently by controlling higher dose of the magnetic particles or intensity of the AMF power.
As for the AMF frequency, it should be noted that lower ones within the range of 50 kHz to 100 kHz of AMF are recommended for human therapy depending on the body cross-section and tissue conductivity [7, 14]. When we use smaller SSA particles, we could overcome the disadvantage of smaller frequency of the AMF by controlling the intensity of power of the AMF.
Our group is now planning to the application to actual cancer patients. SSA and AC frequency was one of the important criteria for magnetite particle preparation. Actual apparatus for cancer patient was already designed and fabricated, that is AC frequency of 110 kHz. Sample C or D was applicable to actual cancer treatment.
In the present study, we observed collateral evidence that the SAR of the magnetite nanoparticles in an external AMF are induced by two heating mechanisms that depends on the SSA of the particles. The critical change of the SAR value was observed at approximately 110 m2/g of the SSA which exists among the 10 nm diameter particles. This is likely due to the structure change of magnetic domain. Additionally, we suggested that heating property of these two mechanisms is defined under the different influences of the frequency and the power of the AC magnetic field.
In conclusion, we provided the basic data for selection of the magnetite particles for the MFH treatment along with the treating part of the body or purpose of the treatment, and we suggested that for the selection of the particles, SSA could be one of the good criteria.
- Overgaard J: Hyperthermic Oncology. 1985, Taylor and Francis, 2: 8-9.Google Scholar
- Kato H, Ishida T: Present and future status of nonivasive selective deep heating using RF in hyperthermia. Med Biol Eng Comput. 1993, 31 Suppl: S2-S11. 10.1007/BF02446643.PubMedView ArticleGoogle Scholar
- Jordan A, Scholz R, Wust P, Shirra H, Schiestel T, Schmidt H, Felix R: . J Magn Magn Mater. 1999, 194: 185-196. 10.1016/S0304-8853(98)00558-7.View ArticleGoogle Scholar
- Shinkai M, Yanase M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnetite cationic liposomes: in vitro study. Jpn J Cancer Res. 1996, 87: 1179-1183.PubMedView ArticleGoogle Scholar
- Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnite cationic liposomes: ex vivo study. Jpn J Cancer Res. 1997, 88: 630-632.PubMedView ArticleGoogle Scholar
- Yanase M, Shinkai M, Honda H, Wakabayashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magnite cationic liposomes: an in vivo study. Jpn J Cancer Res. 1998, 89: 463-469.PubMedView ArticleGoogle Scholar
- Suzuki M, Shinkai M, Honda H, Kobayashi T: Anti-cancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma Res. 2003, 13 (2): 129-135. 10.1097/00008390-200304000-00004.PubMedView ArticleGoogle Scholar
- Shinkai M, Yanase M, Suzuki M, Honda H, Wakabyashi T, Yoshida J, Kobayashi T: Intracellular hyperthermia for cancer using magneic cationic lioosomes. J Magn Magn Mater. 1999, 194: 176-184. 10.1016/S0304-8853(98)00586-1.View ArticleGoogle Scholar
- Ito A, Tanaka K, Shinkai M, Honda H, Matumoto K, Saida T, Kobayashi T: Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Sci. 2003, 94: 308-313. 10.1111/j.1349-7006.2003.tb01438.x.PubMedView ArticleGoogle Scholar
- Matsuoka F, Shinkai M, Honda H, Kubo T, Sugita T, Kobyashi T: Hyperthermia using magnetite cationic liposomes for hamster osteosarcoma. BioMag Res Tech. 2004, 2: 3-10.1186/1477-044X-2-3.View ArticleGoogle Scholar
- Kawai N, Ito A, Nakahara Y, Honda H, Kobayashi T, Futakuchi F, Shirai T, Tozawa K, Kohri K: Complete regression of experimental prostate cancer in nude mice by repeated hyperthermia using magnetite cationic liposomes and a newly developed solenoid containing a ferrite core. The Prostate. 2006, 66: 718-727. 10.1002/pros.20394.PubMedView ArticleGoogle Scholar
- Motoyama J, Yamashita N, Morino T, Tanaka M, Kobayashi T, Honda H: Hyperthermic treatment of DMBA-induced rat mammary cancer using magnetic nanoparticles. BioMag Res Tech. 2008, 6: 2-10.1186/1477-044X-6-2.View ArticleGoogle Scholar
- Jordan A, Scholz R, Wust P, Fähing H, Ferix R: J Magn Magn Mater. 1999, 201: 413-419. 10.1016/S0304-8853(99)00088-8.View ArticleGoogle Scholar
- Shinkai M, Le B, Honda H, Yoshikawa K, Shimizu K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T: Targeting hyperthermia for renal cell carcinoma using human MN antigen-specific magnetoliposome. Jpn J Cancer Res. 2001, 92: 1138-1145.PubMedView ArticleGoogle Scholar
- Babincova M, Leszcznska D, Sourivong P, Čičmanec P, Babinec P: Superparamagnetic gel as a novel materials for electromagnetically induced hyperthermia. J Magn Magn Mater. 2001, 225: 109-112. 10.1016/S0304-8853(00)01237-3.View ArticleGoogle Scholar
- Ma M, Wu Y, Zhou J, Sun Y, Zhang Y, Gu N: Size dependence of specific power absorption of Fe3O4 particles in AC magnetic field. J Magn Magn Mater. 2004, 268: 33-39. 10.1016/S0304-8853(03)00426-8.View ArticleGoogle Scholar
- Jordan A, Wust P, Scholz R, Faeling H, Krause J, Felix R: Scientific and Clinical Application of Magnetic Carriers. Plenum Press, NY, 569-595.
- Mornet S, Vasseur S, Grasset F, Duguet E: Magnetic nanoparticles design for medical diagnosis and therapy. J Mater Chem. 2004, 14: 2161-2175. 10.1039/b402025a.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.