Masaharu Ueno

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.

Release of 5-fluorouracil from thermosensitive magnetoliposomes induced by an electromagnetic field

Abstract Thermosensitive magnetoliposomes (TMs) have been proposed by the authors as a new drug carrier for magnetic targeting (Viroonchatapan et al., Pharm. Res. 12 (1995) 1176–1183; Viroonchatapan et al., Life Sci. 58 (1996) 2251–2261). The present study was carried out to investigate the properties of selective heating and thermosensitive drug release of TMs caused by an electromagnetic field. TMs containing 5-fluorouracil (5-FU) were prepared by reverse-phase evaporation. They were selectively heated by a 500-kHz electromagnetic field in a temperature-controlling unit kept at 37°C, and the properties of single and multiple release of 5-FU from TMs were examined. The results showed that the temperature of TMs could be effectively elevated to 42°C and maintained at this temperature against a cooling effect of the temperature-controlling unit, which mimics an in vivo situation where temperature rise in the site of TM delivery would be hindered by blood flow and surrounding tissues. The release of 5-FU from TMs in response to electromagnetic field-generated heat was accomplished. Moreover, the drug release could be executed several times by multiple exposure to the field. In conclusion, this paper presents for the first time a demonstration of both single and multiple thermosensitive drug release from TMs, induced by an electromagnetic field. It is suggested that TMs would be useful in future cancer treatment by magnetic targeting combined with drug release in response to electromagnetic induced hyperthermia.

Microdialysis Assessment of 5-Fluorouracil Release from Thermosensitive Magnetoliposomes Induced by an Electromagnetic Field in Tumor-Bearing Mice

The current study was designed to evaluate the properties of thermosensitive magnetoliposomes (TMs), a new drug carrier proposed by the authors, in an electromagnetic field pertaining to their selective heating and drug release under an in vivo condition. TMs containing 5-fluorouracil (5-FU) were prepared by reverse-phase evaporation, injected into the tumor mass of B 16-BL6 melanoma in mice, and selectively heated by a 500-kHz electromagnetic field. The release profile of 5-FU from TMs was examined by using a microdialysis technique. The temperature of TMs in the tumor was effectively elevated to 42 degrees C and maintained at this temperature, overcoming the cooling effect of blood flow and surrounding tissues. The release kinetics of 5-FU from TMs was successfully analyzed by physiological modeling, which allows the prediction of intratumor drug concentrations during electromagnetic field exposure under various conditions. In conclusion, this study first demonstrated an in vivo evidence for the electromagnetic field-induced thermosensitive release of a drug from TMs in a tumor with the use of microdialysis.