Preparation and biodistribution of ganglioside GM1-thermosensitive liposomes containing doxorubicin.

Ganglioside GMI-thermosensitive liposomes (GM1-TSL) were prepared from DPPC/DSPC (9 : 1 in molar ratio) and appropriate amount of GM1 by reverse-phase evaporation method. Doxorubicin (DXR)was encapsulated into GM1-TSL with> 98% in trapping efficiency by pH gradient method. The incorporation of 3 or 6 mol% of GM1 to TSL did not affect the temperature-dependent release of DXR from liposomes in vitro. Inclusion of 6 mol% of GM1 endowed TSL with prolonged circulation ability, resulting in increased blood levels of liposomes and decreased RES uptake over 6 hours after i. v. injection to mice. Concomitantly, DXR levels in blood remained high for long time. The combination of DXR-GM1-TSL and the local hyperthermia have been tested for their utility as a temperature sensitive release for DXR in colon 26 tumor-bearing mice. The accumulation of DXR into tumor by local hyperthermia (42°C, 20 min) after injection of DXR-GM1-TSL(GM1 6mol%) was 7 or 2.4 times greater than that after treatment with free DXR or DXR-TSL in combination with hyperthermia, respectively. These results indicate that long-circulating ability is effective for thermosensitive liposomal drug delivery in combination with hyperthermia. This system is expected to be very useful for antitumor therapy.