Drug delivery system using long-circulating thermosensitive liposomes in combination with local hyperthermia

Long-circulating, thrmosensitive liposomes (TSL, 200 nm in mean diameter) were prepared from GM1/DPPC/DSPC or PEG-PE/DPPC/DSPC. Doxorubicin (DXR) was encapsulated into GM1-TSL with >98% or PEG-TSL with >90% in trapping efficiency by pH gradient method, respectively. DXR was released from both type of TSL in a temperature-dependent manner in vitro. Inclusion of 6 mol% of GM1 or 3 mol% of PEG-PE endowed TSL with prolonged circulation ability resulting in increased blood levels of liposomes and decreased RES uptake after injection to mice. Concomitantly, high DXR levels in blood were maintained for long time. The combination of DXR-long-circulating TSL and the local hyperthermia have been tested for their utility as a temperature sensitive release for DXR in colon 26 tumor-bearing mice. Accumulation of DXR into tumor tissue by local hyperthermia after injection of DXR-long-circulating TSL was significantly higher than that of DXR-bare TSL or free DXR, and resulted in effective tumor growth retardation and increased survival time. 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.