Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases.
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.
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A high activation energy (slope of the Arrhenius plot) enables sufficient GC release at 37°C and minimal release at 2-8°C.
“Such a high slope enables a sufficient release at 37°C (needed to achieve efficacy), concomitant with a minimal release at 2–8°C (to ensure long-term storage shelf life), both of which were demonstrated for Doxil [17], [19].”
From Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids (2011) · cites this paper as [17]
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- Authors
- Haran, G., Cohen, R., Bar, L. K., & Barenholz, Y.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Barenholz, Yechezkel
- Venue
- Biochimica et Biophysica Acta (BBA) - Biomembranes
- Publisher
- Elsevier BV
- Published
- 1993-09
- Volume
- 1151
- Issue
- 2
- Pages
- 201-215
- ISSN
- 0005-2736 (ISSN-L)
- OpenAlex
- W2036944284
- Cited by
- 934
- References
- 44
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 19 · 2023: 29 · 2022: 33 · 2021: 39 · 2020: 33 · 2019: 34 · 2018: 45 · 2017: 38 · 2016: 55 · 2015: 35 · 2014: 63 · 2013: 54 · 2012: 42
- FWCI
- 10.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Biomembranes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- liposome encapsulation, remote loading, anthracyclines, doxorubicin, acridine orange, base exchange, ammonium, liposome stability, liposome lipid composition
- MeSH terms
- Ammonia, Ammonium Sulfate, Doxorubicin, Drug Stability, Electric Conductivity, Hydrogen-Ion Concentration, Liposomes, Quality Control, Technology, Pharmaceutical, 1,2-Dipalmitoylphosphatidylcholine
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