Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient

• Published in: Biochimica et biophysica acta Vol. 1758; no. 10; pp. 1633 - 1640
• Main Authors: Fritze, Andreas, Hens, Felicitas, Kimpfler, Andrea, Schubert, Rolf, Peschka-Süss, Regine
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2006
• Subjects: Acetates - chemistry; Ammonium Sulfate - chemistry; Cholesterol - chemistry; Citrates - chemistry; Citric Acid - chemistry; Cryo-electron microscopy; Diammonium hydrogen phosphate; Doxorubicin; Doxorubicin - chemistry; EPC/cholesterol liposome; Hydrogen-Ion Concentration; Liposomes - chemical synthesis; Microscopy, Electron, Transmission; pH-triggered release; Phosphates - chemistry; Phosphatidylcholines - chemistry; Quaternary Ammonium Compounds - chemistry; Remote loading; Sodium - chemistry; Sodium Acetate - chemistry; Sulfates - chemistry; Diammonium hydrogen phosphate; EPC/cholesterol liposome; Remote loading; Doxorubicin; Cryo-electron microscopy; pH-triggered release
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/j.bbamem.2006.05.028

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-dependant 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 °C or 30% at 37 °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.