Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases

Gilad Haran, Rivka Cohen, Liliana K. Bar, Yechezkel Barenholz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

825 Scopus citations

Abstract

Gradients of ammonium sulfate in liposomes [(NH4)2SO4]lip.>[(NH4)2SO4]med. were used to obtain 'active' loading of amphipathic weak bases into the aqueous compartment of liposomes. The loading is a result of the base exchange with the ammonium ions. This approach was applied to encapsulate anthracyclines and acridine orange inside the liposomes at very high efficiency (>90%). Doxorubicin was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold the doxorubicin concentration in the remote loading medium. Most of the intraliposomal doxorubicin was present in an aggregated state. The active entrapment and loading stability were dependent on liposome lipid composition, lipid quality, medium composition and temperature, as well as on the pKa and hydrophobicity of the base. The ammonium sulfate gradient approach differs from most other chemical approaches used for remote loading of liposomes, since it neither requires preparation of the liposomes in acidic pH, nor to alkalinize the extraliposomal aqueous phase. The stability of the ammonium ion gradient is related to the low permeability of its counterion, the sulfate, which also stabilizes anthracycline accumulation for prolonged storage periods (>6 months) due to the aggregation and gelation of anthracycline sulfate salt.

Original languageEnglish
Pages (from-to)201-215
Number of pages15
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1151
Issue number2
DOIs
StatePublished - 19 Sep 1993

Keywords

  • Ammonium sulphate gradient
  • Amphipathic base
  • Doxorubicin
  • Drug delivery
  • Liposome
  • Remote loading

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