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 local hyperthermia was achieved by using long-circulating, thermosensitive liposomes (TSL) composed of dipalmitoyl phosphatidylcholine (DPPC)/distearoyl phosphatidylcholine (DSPC) (9:1, m/m) and 3 mol% amphipathic polyethylene glycol (PEG) in colon 26-bearing mice. Inclusion of 3 mol% of distearoyl phosphatidylethanolamine derivatives of PEG (DSPE-PEG, amphipathic PEG) with a mean molecular weight of 1000 or 5000 in DPPC/DSPC liposomes resulted in decreased reticuloendothelial system (RES) uptake and a concomitant prolongation of circulation time, affording sustained increased blood levels of the liposomes. Concomitantly, DXR levels in blood were also kept high over a long period. The presence of amphipathic PEG did not interfere with the encapsulation of DXR by the pH gradient method (> 90% trapping efficiency) or with the temperature-dependent drug release from the liposomes. The optimal size of these liposomes was 180-200 nm in mean diameter for thermosensitive drug release and prolonged circulation time. The DXR levels in the tumor after injection of long-circulating TSL (DXR-PEG1000TSL or DXR-PEG5000TSL, at a dose of 5 mg DXR/kg) with local hyperthermia were much higher than after treatment with DXR-TSL lacking PEG or with free DXR, reaching 7.0-8.5 DXR micrograms/g tumor (approximately 2 times or 6 times higher than that of DXR-TSL or free DXR, respectively). Furthermore, the combination of DXR-PEGTSL and hyperthermia effectively retarded tumor growth and increased survival time.(ABSTRACT TRUNCATED AT 250 WORDS)
Unezaki
S
S
Department of Pharmacy, Tokyo Medical College Hospital, Japan.
Maruyama
K
K
Takahashi
N
N
Koyama
M
M
Yuda
T
T
Suginaka
A
A
Iwatsuru
M
M
D015060:1,2-Dipalmitoylphosphatidylcholine; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D008081:Liposomes; D010713:Phosphatidylcholines; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C010942:1,2-distearoyllecithin