Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: An in vivo Study
Mitsugu Yanase,1 Masashige Shinkai,1 Hiroyuki Honda,1 Toshihiko Wakabayashi,2 Jun Yoshida 2 and Takeshi Kobayashi1, 3
Department of Biotechnology, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8603 and 2Department ofNeurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550
The effect of hyperthermia on solid glioma tissue formed subcutaneously in the left femoral region of female F344 rats was investigated. Magnetite cationic liposomes (MCLs), which have a positive surface charge, were used as heating mediators for intracellular hyperthermia. MCLs were injected into thesolid tumors, which were then subjected to irradiation by an alternating magnetic field (118 kHz, 384 Oe). The rats were divided into four groups, which received no irradiation (control: group I), or irradiation for 30 min given once (group II), twice (group III) or three times (group IV), and the hyperthermic effect on tumor growth was evaluated. Complete tumor regression was observed in 87.5%of the rats in group IV. In the other groups, tumors completely regressed in 20 and 60% of the rats in groups II and III, respectively. Histological observations showed that in group I tumors, MCLs were localized only around the point where they were injected, while in group II tumors they were a little more dispersed. In the cases of group III and IV tumors, however, the distribution of the MCLswas found to be widespread, and necrotic cells were observed throughout almost the entire tumor tissue. The high percentage of complete regression of group IV is considered to be due to this wide distribution of the MCLs. Furthermore, the treated rats showed no severe side-effects. These results suggest that our magnetic particles are potentially effective tools for the treatment of solid tumors.Key words: Magnetite cationic liposomes — Magnetite — Intracellular hyperthermia — Glioma cells — Induction heating
Conventional therapies commonly employed in cancer treatment, including surgery, radiotherapy, and chemotherapy, are not very effective in the treatment of certain cancers such as glioblastoma, for which a novel and effective method of treatment is desired. Hyperthermia is seen asa promising therapy for such cancers.1) Hyperthermia therapy is based on the fact that tumor cells are more sensitive to temperature than normal tissue cells.2–4) However, the difficulty of achieving the necessary selective heating remains an important technical problem to be solved.5, 6) Implantable needles have been developed for use as heating mediators in hyperthermia therapy. However, theprocedure is very painful for the patient because many needles must be implanted to achieve homogeneous heating of tumor tissue.7, 8) If fine particles can be used as heating mediators instead of needles, this difficulty may be overcome. For this reason, we developed submicronsized magnetite particles for heating tumor cells.9) Because magnetite is ferromagnetic, heat is generated within theparticles under an alternating magnetic field,10) and they are easily incorporated into cells since their diameter is only 10–40 nm. For administering magnetite particles to the body, we also developed particles coated with a liposomal mem3
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brane, ‘magnetoliposomes’ (MLs), and investigated both their magnetic properties and their application forhyperthermic simulation.10, 11) Although the MLs are biocompatible and are highly dispersed in an aqueous solution, in vitro experiments using glioma cells as a tumor model revealed that their adsorption and accumulation into glioma cells was insufficient. Recently, we developed ‘magnetite cationic liposomes’ (MCLs) with improved adsorption and accumulation properties.12) MCLs, which have a...