ENHANCED DELIVERY OF DOXORUBICIN TO TUMOR BY LONG-CIRCULATING THERMOSENSITIVE LIPOSOMES AND LOCAL HYPERTHERMIA

Doxorubicin (DXR) was encapsulated in long-circulating, thermosensitive liposomes (180-200 nm), prepared from dipalmitoyl-phosphatidylcholine (DPPC)/distearoylphosphatidylcholine (DSPC) (9:1 (m/m)) and 6 mol% of ganglioside G(M1) (G(M1)), with 95-98% entrapping efficiency by the pH-gradient method. 45% of the entrapped DXR was released from these G(M1)/DPPC/DSPC liposomes by incubation at 42-degrees-C for 5 min in 20% serum or saline (this degree of release was lower than that of hydrophilic drugs such as cisplatin, due to the basic and amphiphilic nature of DXR). Inclusion of G(M1) (6 mol%) endowed DPPC/DSPC liposomes with prolonged circulation ability, resulting in increased blood levels of liposomes and decreased reticuloendothelial system uptake over 6 h after injection. Concomitantly, DXR levels in blood remained high for long time. Accumulation of DXR into tumor tissue of tumor-bearing mice (mouse colon carcinoma 26) by local hyperthermia after injection of DXR loaded, long-circulating, thermosensitive (DXR-G(M1)/DPPC/DSPC) liposomes was 2.5-times or 6-times higher than that after treatment with DXR-DPPC/DSPC liposomes or free DXR in combination with hyperthermia, respectively. Furthermore, the treatment with DXR-G(M1)/DPPC/DSPC liposomes and hyperthermia resulted in effective tumor-growth retardation and increased survival time. Our results indicate that the combination of drug-loaded, long-circulating, thermosensitive liposomes with local hyperthermia at the tumor site could be clinically useful for delivering a wide range of chemotherapeutic agents in the treatment of solid tumors.