Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery.
Open accessAbstract
Phase transitions in closed vesicles, i.e., microenvironments defined by the size of the vesicle, its contents, and permeability of its membrane are becoming increasingly important in several scientific disciplines including catalysis, growth of small crystals, cell function studies, and drug delivery. The membrane composed from lipid bilayer is in general impermeable to ions and larger hydrophilic ions. Ion transport can be regulated by ionophores while permeation of neutral and weakly hydrophobic molecules can be controlled by concentration gradients. Some weak acids or bases, however, can be transported through the membrane due to various gradients, such as electrical, ionic (pH) or specific salt (chemical potential) gradients. Upon permeation of appropriate species and reaction with the encapsulated species precipitation may occur in the vesicle interior. Alternatively, these molecules can also associate with the leaflets of the bilayer according to the transmembrane potential. Efficient liposomal therapeutics require high drug to lipid ratios and drug molecules should have, especially when associated with long circulating liposomes, low leakage rates. In this article we present very efficient encapsulation of two drugs via their intraliposomal precipitation, characterize the state of encapsulated drug within the liposome and try to fit the experimental data with a recently developed theoretical model. Nice agreement between a model which is based on chemical potential equilibration of membrane permeable species with experimental data was observed. The high loading efficiencies, however are only necessary but not sufficient condition for effective therapies. If adequate drug retention within liposomes, especially in the case of long-circulating ones, is not achieved, the therapeutic index decreases substantially. Anticancer drug doxorubicin precipitates in the liposome interior in a form of gel with low solubility product and practically does not leak out in blood circulation in the scale of days. With an antibiotic, ciprofloxacin, the high loading efficacy and test tube stability is not reproduced in in vitro plasma leakage assays and in vivo. We believe that the reasons are higher solubility product of precipitated drug in the liposome, larger fraction of neutral molecules due closer pK values of the drug with the pH conditions in the solutions and high membrane permeability of this molecule. High resolution cryoEM shows that encapsulated anticancer agent doxorubicin is precipitated in the form of bundles of parallel fibers while antibiotic ciprofloxacin shows globular precipitate. Doxorubicin gelatin also causes the change of vesicle shape.
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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 [19]
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- Authors
- Lasic, D. D., Čeh, B., Stuart, M. C. A., Guo, L., Frederik, P. M., & Barenholz, Y.
- Affiliations
- University of Ljubljana (SI)
- Hebrew University of Jerusalem (IL)
- Venue
- Biochimica et Biophysica Acta (BBA) - Biomembranes
- Publisher
- Elsevier BV
- Published
- 1995-11
- Volume
- 1239
- Issue
- 2
- Pages
- 145-156
- ISSN
- 0005-2736 (ISSN-L)
- OpenAlex
- W2040876516
- Cited by
- 209
- References
- 20
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 10 · 2020: 6 · 2019: 2 · 2018: 10 · 2017: 4 · 2016: 9 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 11
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- liposomes, doxorubicin, ciprofloxacin, encapsulation efficiency, drug leakage, long-circulating liposomes, solubility product, pH gradient, membrane permeability, drug retention
- MeSH terms
- Animals, Ciprofloxacin, Doxorubicin, Drug Carriers, Gels, Liposomes, Models, Chemical, Permeability, Scattering, Radiation, X-Rays, Drug Delivery Systems, Rats
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