(Invited) Application of Ferrite Nanoparticles to Magnetic Hyperthermia

Hyperthermia (thermotherapy), in which cancer cells are treated with heat of approximately 43°C, has recently received attention as a promising approach to cancer therapy because hyperthermia is non-invasive and has very few side effects, compared to surgical resection, chemotherapy, and radiation therapy. In hyperthermia using magnetic nanoparticles and an alternating magnetic field of a few hundred kHz, heat generation is derived just from their magnetic property. Magnetic nanoparticles, in particular iron oxide such as magnetite (Fe­ 3O4) or maghemite (γ-Fe2O3), are generally used as heat sources as they have the advantages of high biocompatibility and relatively large magnetization. We have been investigating the synthesis of ferrite nanoparticles and their in vitro and in vivo evaluation for magnetic hyperthermia. We demonstrated the synthesis of Fe3O4 nanoparticles with the size tuned in the range of 10 to 40 nm in mean diameter by chemical reaction in an aqueous solution containing iron(II) and iron(III) salts at various ratios with 1,6-hexanediamine as a base [1]. Here organic amines are considered to serve not only as a base but also as a protective reagent. Magnetic properties of Fe3O4 nanoparticles can be controlled by the particle diameter [1]. Considering to their biomedical application, Fe3O4 nanoparticles were evaluated for their safety by using mouse embryonic stem (mES) cells from the viewpoint of viability and keeping undifferentiated state of mES cells [2]. In addition, we demonstrated that the use of spermine instead of 1,6-hexanediamine is also useful for the synthesis and found that Fe3O4 nanoparticles with diameter of approximately 40 nm prepared with 1,6-hexanediamine and spermine possess negative and positive charge, respectively [3]. With human breast cancer MCF-7 cells, we demonstrated that the nanoparticles with positive charge showed higher internalization into MCF-7 cells than the nanoparticles with negative charge [3], and that ~40-nm Fe3O4 nanoparticles showed a higher heating efficacy than did ~10-nm Fe3O4 nanoparticles when MCF-7 cells containing nanoparticles were subjected to alternating magnetic field [4]. With mesothelioma cells that are of an asbestos-related fatal cancer with no effective treatment, we demonstrated the potential of Fe3O4 nanoparticles for future application to mesothelioma treatment via the following two approaches: (i) the use of specific apoptotic effect of Fe3O4 nanoparticles on biphasic MSTO-211H cells and (ii) the use of heat generation by Fe3O4 nanoparticles subjected to alternating magnetic field, which induced a high degree of cell mortality in all three major histologic subtypes of mesothelioma cells (epithelioid NCI-H28, sarcomatoid NCI-H2052, and biphasic MSTO-211H cells) [5]. For in vivo investigation, we designed optimized multifunctional Fe3O4 nanoparticles, composed of Fe3O4 nanoparticles and photosensitizer conjugated hyaluronic acid, to achieve enhanced tumor diagnosis and therapy. We successfully detected tumors implanted in mice via magnetic resonance imaging and optical imaging, and demonstrated the photodynamic/hyperthermia-combined therapeutic efficacy of the functionalized nanoparticles with synergistically enhanced efficacy against cancer [6]. Aiming to effective heat generation, we focused our attention on other ferrite nanoparticles. In CoFe2O4 nanoparticles, which were synthesized by chemical reaction in an aqueous solution containing cobalt(II) and iron(III) salts with spermine as a base, we demonstrated that an increase in coercivity derived from the substitution of Fe2+ in Fe3O4 with Co2+ facilitated the ability of the nanoparticles to induce cell death in human breast cancer cells under alternating magnetic field [7]. [1] H. Iida, K. Takayanagi, T. Nakanishi, T. Osaka, J. Colloid Interface Sci., 314 (2007) 274. [2] C. Shundo, H. Zhang, T. Nakanishi, T. Osaka, Colloids Surf. B, 97 (2012) 221. [3] T. Osaka, T. Nakanishi, S. Shanmugam, S. Takahama, H. Zhang, Colloids Surf. B, 71 (2009) 325. [4] D. Baba, Y. Seiko, T. Nakanishi, H. Zhang, A. Arakaki, T. Matsunaga, T. Osaka, Colloids Surf. B, 95 (2012) 254. [5] S. Matsuda, A. Hitsuji, T. Nakanishi, H. Zhang, A. Tanaka, H. Matsuda, T. Osaka, ACS Biomater. Sci. Eng., 1 (2015) 632. [6] K.S. Kim, J.Y. Kim, J.Y. Lee, S. Matsuda, S. Hideshima, Y. Mori, T. Osaka, K. Na, submitted. [7] S. Matsuda, T. Nakanishi, K. Kaneko, T. Osaka, Electrochim. Acta, 183 (2015) 153.