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

Doxorubicin (DXR) was encapsulated in long-circulating, thermosensitiv e liposomes (180-200 nm), prepared from dipalmitoyl-phosphatidylcholin e (DPPC)/distearoylphosphatidylcholine (DSPC) (9:1 (m/m)) and 6 mol% o f 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 hydro philic drugs such as cisplatin, due to the basic and amphiphilic natur e of DXR). Inclusion of G(M1) (6 mol%) endowed DPPC/DSPC liposomes wit h prolonged circulation ability, resulting in increased blood levels o f liposomes and decreased reticuloendothelial system uptake over 6 h a fter injection. Concomitantly, DXR levels in blood remained high for l ong time. Accumulation of DXR into tumor tissue of tumor-bearing mice (mouse colon carcinoma 26) by local hyperthermia after injection of DX R loaded, long-circulating, thermosensitive (DXR-G(M1)/DPPC/DSPC) lipo somes was 2.5-times or 6-times higher than that after treatment with D XR-DPPC/DSPC liposomes or free DXR in combination with hyperthermia, r espectively. Furthermore, the treatment with DXR-G(M1)/DPPC/DSPC lipos omes and hyperthermia resulted in effective tumor-growth retardation a nd 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 deliver ing a wide range of chemotherapeutic agents in the treatment of solid tumors.