Hideo Nagae

Preparation and characterization of dextran magnetite-incorporated thermosensitive liposomes: an on-line flow system for quantifying magnetic responsiveness.

AbstractPurpose. Dextran magnetite (DM)-incorporated thermosensitive liposomes, namely thermosensitive magnetoliposomes (TMs), were prepared and characterized in order to investigate their possibility for magnetic drug targeting.nMethods. TMs containing calcein were prepared at various DM concentrations by reverse-phase evaporation of dipalmitoylphosphatidylcholine (DPPC). They were evaluated for their physicochemical properties including size, DM capture, magnetite distribution within liposomes, and temperature-dependent calcein release. Moreover, a novel on-line flow apparatus with a sample injector, a coil of tubing placed in an electromagnet, and a fluorescence detector was developed for quantifying the magnetic responsiveness of TMs. This device allowed us a real-time measurement of percentage holding of TMs by magnetic field.nResults. Due to water-soluble property of DM, higher contents of magnetite up to 490 mg per mmol DPPC were successfully incorporated into the liposomes with DM than with conventional magnetite (Fe3O4). Thermosensitivity and lipid integrity of TMs were not influenced by inclusion of DM. Using the on-line flow system, percentage holding of TMs by magnetic field was shown to vary with several factors; it increases as the magnetic field strength increases, the fluid flow rate decreases, the magnetite content increases, and the liposome concentration increases. Typically, at 490 mg incorporated magnetite per mmol DPPC, 0.5 ml/min-fluid flow rate, and high magnetic field strength (≥10 kiloGauss), approximately 100% of TMs were found to be held.nConclusions. The TMs were suggested to be useful in future cancer treatment by magnetic targeting combined with drug release in response to hyperthermia.

Selective induction hyperthermia following transcatheter arterial embolization with a mixture of nano-sized magnetic particles (ferucarbotran) and embolic materials: feasibility study in rabbits.

PurposeTo evaluate the possibility of selective hyperthermia following transcatheter arterial embolization (TAE) with ferucarbotran using a newly developed inductive heating (IH) device.Materials and methodsTwelve Japanese white rabbits were separated into four groups: those treated with TAE using a mixture of ferucarbotran and lipiodol (F-L group); those treated with ferucarbotran and gelatin sponge powder; those treated with saline and lipiodol; and a control group. These four groups received IH. Nine rabbits with renal VX2 carcinoma were separated into three groups: IH after TAE (IH-TAE tumor), TAE without IH (TAE tumor), and no treatment (control tumor). The temperature of the tumor was kept at 45°C for 20 min. The therapeutic effect was pathologically evaluated by TUNEL staining.ResultsIn the heating rates of the kidney, the F-L group showed significantly greater values than the group in which iron was not used. In the IH-TAE tumor group, tumors could be selectively heated. In TUNEL staining, the IH-TAE tumor and TAE tumor groups showed significantly greater values of apoptosis rate than in the control tumor group.ConclusionIH following TAE with a mixture of ferucarbotran and lipiodol was capable of inducing selective hyperthermia with our device. However, further investigation is needed to confirm its safety and effectiveness in the treatment of malignant neoplasms in humans.

Antitumor activity of selective hyperthermia in tumor-bearing rats using thermosensitive magnetoliposomes as a new hyperthermic material

AbstractThe antitumor activity of dextran magnetite (DM)-incorporating thermosensitive liposomes, namely thermosensitive magnetoliposomes (TMs), as a new hyperthermic material was examined in rats bearing AH60C tumors. TMs were injected at an iron concentration of 15 mg per cm3 tumor into AH60C tumors placed subcutaneously in the backs of Donryu rats. After injection, the whole body of the rat (treated group) was exposed to a 500-kHz electromagnetic field generated by inductive heating. The treated group was further divided into once- and twice-treated groups in order to examine whether repetitive hyperthermia is possible after a single TM injection. A control group also received a TM injection but was not treated with hyperthermia. In the heated groups, there was a marked temperature rise inside the tumor up to 42°C within 7 min, but surrounding tissues were not heated. The inhibition of the growth of AH60C tumor in the treated groups was significantly greater than in the control group (P <. 01). Histolo...

Antitumor effects of inductive hyperthermia using magnetic ferucarbotran nanoparticles on human lung cancer xenografts in nude mice

Background The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line. Methods We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events. Results Intratumor temperature rose rapidly and was maintained at 43°C–45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis. Conclusion Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia.

Development of new cancer treatment using approved MRI contrast agent and induction heating device

MRI contrast agents, Feridex and Resovist have superparamagnetic substance as an active ingredients. Feridex does not show temperature rise under AC magnetic field. In contrast Resovist shows temperature rise under the same condition. W e simulated the optimum frequency on Resovist using phantom and found it is 140 kHz. However treatable cancer volume was limited to 9cm3. We tried a fractionation of Resovist. One of the fractions was found to be effective by more than 6 times compared to the drug by itself. This result suggests that the hyperthermia in combination with the fraction and induction heating device is a promising treatment for cancer.