Magnetic nanoparticles have been widely used in biological and medical fields. For instance, magnetic separation is used to separate certain biomaterials [1
] and/or cells [2
] by using biologically labeled magnetic beads. In the medical field, certain types of magnetic dispersion are used as a contrast agent in magnetic resonance imaging (MRI) diagnosis [4
]. Recently, magnetic nanoparticles have also been investigated for therapeutic purposes such as hyperthermic treatment [5
Hyperthermic treatments have been used for many years, particularly in anticancer therapy [6
]. Typically, there are 2 ranges of targeting temperature used in such treatment. High temperatures (greater than 50°C) kill targeted tissue directly. Such direct heating methods using needle-type interstitial antenna materials are effective for inducing hyperthermia in local regions; however, these technologies are less effective for larger areas of tissue [7
]. Lower temperatures of approximately 40°C to 43°C are also associated with an anticancer effect. There are several heating techniques employed in hyperthermic treatments using such a temperature range. For example, radiofrequency (RF) electric field application is one of the approved methods for cancer treatment. However, the effectiveness of this technique varies according to tumor size and the depth of the tumor region from the body surface. Furthermore, it is sometimes difficult to focus on the exact location of the tumor [8
]. Microwaves, ultrasound applied as a heating method, are also used for inducing hyperthermia. For such hyperthermic therapy, magnetic nanoparticles have also used been used as a heating mediator. The use of these particles is based on fact that such multidomain ferro- or ferri-magnetic materials are heated by an alternating magnetic field due to hysteresis losses [9
]. Single domain particles of magnetite can also generate heat by relaxation loss, not hysteresis loss, under irradiation of alternating magnetic field. Ten nanometer of diameter is boundary size to allocate particles between single-domain and multi-domain. Optimal diameter of magnetic nanoparticle for magnetic nanoparticle-mediated hyperthermia should be investigated in detail.
Our group has pioneered one of these technologies in order to selectively heat tumor regions [10
]. We have introduced cationic liposome technology in order to enhance the surface interaction between cells and heating mediator, and thereby improve its localization. In previous animal studies, we have demonstrated the efficacy of hyperthermia induce using magnetite cationic liposomes (MCLs) [10
] in several types of tumor model; for instance, B16 melanoma in mice [13
], T9 glioma in rats [12
], osteosarcoma in hamsters [16
], MM46 mouse mammary carcinoma [17
], PLS 10 rat prostate cancer [18
], and VX-7 squamous cell carcinoma in rabbit tongue [19
]. Furthermore, we have described the capability of immunologic reactivity in cancer therapy, which was enhanced by increasing the amount of heat-shock protein 70 (HSP70), following hyperthermic treatment with MCLs [20
In several transplantable tumor models mentioned above, the magnetite nanoparticle-mediated hyperthermia proposed by us was found to be very effective for inducing complete tumor regression. In such models, however, transplantable cell is an explanted cell. To use the hyperthermia for human patients, the effect of the hyperthermia should be demonstrated by the use of more practical tumor model. We focused on oncogene transgenic mice as spontaneous tumor model and complete tumor regression of malignant melanoma induced by the oncogene ret was achieved by the hyperthermia. As a next step, we investigated here the application to carcinogen-induced spontaneous tumor models as a practical tumor model which can simulate practical tumor in the human patient.
7,12-Dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer has been widely exploited in cancer studies for many years, since it was first reported by Huggins et al. [23
]. This model is very useful as a spontaneous cancer model, since blood vessels and lymphoducts surrounding the tumor tissue are likely to simulate human cancer. In this study, we applied our hyperthermic treatment system with the MCLs to DMBA-induced rat mammary cancer model.