ENHANCED DELIVERY AND ANTITUMOR-ACTIVITY OF DOXORUBICIN USING LONG-CIRCULATING THERMOSENSITIVE LIPOSOMES CONTAINING AMPHIPATHIC POLYETHYLENE-GLYCOL IN COMBINATION WITH LOCAL HYPERTHERMIA
S. Unezaki et al., ENHANCED DELIVERY AND ANTITUMOR-ACTIVITY OF DOXORUBICIN USING LONG-CIRCULATING THERMOSENSITIVE LIPOSOMES CONTAINING AMPHIPATHIC POLYETHYLENE-GLYCOL IN COMBINATION WITH LOCAL HYPERTHERMIA, Pharmaceutical research, 11(8), 1994, pp. 1180-1185
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.