K. Maruyama et al., ENHANCED DELIVERY OF DOXORUBICIN TO TUMOR BY LONG-CIRCULATING THERMOSENSITIVE LIPOSOMES AND LOCAL HYPERTHERMIA, Biochimica et biophysica acta, 1149(2), 1993, pp. 209-216
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.