Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient.
This study examines a new method for the remote loading of doxorubicin into liposomes. It was shown that doxorubicin can be loaded to a level of up to 98% into large unilamellar vesicles composed of egg phosphatidylcholine/cholesterol (7/3 mol/mol) with a transmembrane phosphate gradient. The different encapsulation efficiencies which were achieved with ammonium salts (citrate 100%, phosphate 98%, sulfate 95%, acetate 77%) were significantly higher as compared to the loading via sodium salts (citrate 54%, phosphate 52%, sulfate 44%, acetate 16%). Various factors, including pH-value, buffer capacity, solubility of doxorubicin in different salt solutions and base counter-flow, which likely has an influence on drug accumulation in the intraliposomal interior are taken into account. In contrast to other methods, the newly developed remote loading method exhibits a pH-dependent drug release property which may be effective in tumor tissues. At physiological pH-value doxorubicin is retained in the liposomes, whereas drug release is achieved by lowering the pH to 5.5 (approximately 25% release at 25 degrees C or 30% at 37 degrees C within two h). The DXR release of liposomes which were loaded via a sulfate gradient showed a maximum of 3% at pH 5.5.
Fritze
Andreas
A
Department of Pharmaceutical Technology and Biopharmacy, Albert-Ludwigs University, Stefan-Meier-Str. 19, 79104 Freiburg, Germany.
Hens
Felicitas
F
Kimpfler
Andrea
A
Schubert
Rolf
R
Peschka-Süss
Regine
R
D000085:Acetates / Q000737:chemistry; D000645:Ammonium Sulfate / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D002951:Citrates / Q000737:chemistry; D019343:Citric Acid / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000138:chemical synthesis*; D046529:Microscopy, Electron, Transmission; D010710:Phosphates / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D019346:Sodium Acetate / Q000737:chemistry; D000077559:Sodium Citrate; D013431:Sulfates / Q000737:chemistry
D000085:Acetates; D002951:Citrates; D008081:Liposomes; D010710:Phosphates; D010713:Phosphatidylcholines; D000644:Quaternary Ammonium Compounds; D013431:Sulfates; C024788:ammonium phosphate; C012036:sodium sulfate; D000077559:Sodium Citrate; D019343:Citric Acid; D019346:Sodium Acetate; C481046:ammonium citrate; D004317:Doxorubicin; D002784:Cholesterol; D012964:Sodium; C018824:ammonium acetate; C018279:sodium phosphate; D000645:Ammonium Sulfate