ENHANCED DELIVERY AND ANTITUMOR-ACTIVITY OF DOXORUBICIN USING LONG-CIRCULATING THERMOSENSITIVE LIPOSOMES CONTAINING AMPHIPATHIC POLYETHYLENE-GLYCOL IN COMBINATION WITH LOCAL HYPERTHERMIA

Enhanced delivery of doxorubicin (DXR) to a solid tumor subjected to l ocal hyperthermia was achieved by using long-circulating, thermosensit ive liposomes (TSL) composed of dipalmitoyl phosphatidylcholine (DPPC) /distearoyl phosphatidylcholine (DSPC) (9:1, m/m) and 3 mol% amphipath ic polyethylene glycol (PEG) in colon 26-bearing mice. Inclusion of 3 mol% of distearoyl phosphatidylethanolamine derivatives of PEG (DSPE-P EG, amphipathic PEG) with a mean molecular weight of 1000 or 5000 in D PPC/DSPC liposomes resulted in decreased reticuloendothelial system (R ES) uptake and a concomitant prolongation of circulation time, affordi ng sustained increased blood levels of the liposomes. Concomitantly, D XR levels in blood were also kept high over a long period. The presenc e of amphipathic PEG did not interfere with the encapsulation of DXR b y the pH gradient method (>90% trapping efficiency) or with the temper ature-dependent drug release from the liposomes. The optimal size of t hese liposomes was 180-200 nm in mean diameter for thermosensitive dru g release and prolonged circulation time. The DXR levels in the tumor after injection of long-circulating TSL (DXR-PEG1000TSL or DXR-PEG5000 TSL, at a dose of 5 mg DXR/kg) with local hyperthermia were much highe r than after treatment with DXR-TSL lacking PEG or with free DXR, reac hing 7.0-8.5 DXR mu g/g tumor (approximately 2 times or 6 times higher than that of DXR-TSL or free DXR, respectively). Furthermore, the com bination of DXR-PEGTSL and hyperthermia effectively retarded tumor gro wth and increased survival time. Our results indicate that the combina tion of drug-loaded, long-circulating, thermosensitive liposomes with local hyperthermia at the tumor site could be clinically useful for de livering a wide range of chemotherapeutic agents in the treatment of s olid tumors.