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Liposomes for Drug Delivery: from Physico-chemical Studies to Applications
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Physical Chemistry.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Physico-chemical characterisation of structure and stability of liposomes intended for drug delivery is the central issue in this thesis. In addition, targeted liposomes to be used in boron neutron capture therapy (BNCT) were developed.

Lysolipids and fatty acids are products formed upon hydrolysis of PC-lipids. The aggregate structure formed upon mixing lysolipids, fatty acids and EPC were characterised by means of cryo-TEM. A relatively monodisperse population of unilamellar liposomes was detected in mixtures containing equimolar concentration of the three components.

The interactions between alternative steric stabilisers (PEO-PPO-PEO copolymers) and conventional PC-and pH-sensitive PE-liposomes were investigated. Whereas the PE-liposomes could be stabilised by the PEO-PPO-PEO copolymers, the PC-liposomes showed an enhanced permeability concomitant with the PEO-PPO-PEO adsorption.

Permeability effects induced by different PEG-stabilisers on EPC liposomes were shown to be dependent on the length of the PEG chain but also on the linkage used to connect the PEG polymer with the hydrophobic membrane anchor.

An efficient drug delivery requires, in most cases, an accumulation of the drug in the cell cytoplasm. The mechanism behind cytosolic drug delivery from pH-sensitive liposomes was investigated. The results suggest that a destabilisation of the endosome membrane, due to an incorporation of non-lamellar forming lipids, may allow the drug to be released.

Furthermore, sterically stabilised liposomes intended for targeted BNCT have been characterised and optimised concerning loading and retention of boronated drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 71
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 826
Keywords [en]
Physical chemistry, liposome, steric stabilisation, BNCT, cryo-TEM, EGF, targeting, stability, permeability, pH-sensitive liposomes, triggered release
Keywords [sv]
Fysikalisk kemi
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-3390ISBN: 91-554-5592-1 (print)OAI: oai:DiVA.org:uu-3390DiVA, id: diva2:162632
Public defence
2003-05-23, B41, BMC, Uppsala, 10:15
Opponent
Supervisors
Available from: 2003-04-30 Created: 2003-04-30Bibliographically approved
List of papers
1. Aggregate structure in dilute aqueous dispersions of phospholipids, fatty acids and lysophospholipids
Open this publication in new window or tab >>Aggregate structure in dilute aqueous dispersions of phospholipids, fatty acids and lysophospholipids
2001 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 17, no 11, p. 3245-3253Article in journal (Refereed) Published
Abstract [en]

Cryo-transmission electron microscopy (cryo-TEM) was employed to investigate the aggregate structure in dilute aqueous dispersions of egg-phosphatidylcholine (EPC), oleic acid (OA), and the lysophospholipid monooleoylphosphatidylcholine (MOPC). At physiological pH and salt concentration, a relatively monodisperse population of unilamellar liposomes was detected in mixtures containing equimolar concentrations of the three components. Threadlike micelles constituted the dominant aggregate structure in samples containing high concentrations of MOPC. Excess fatty acid forced, on the other hand, the system toward structures with net negative curvature. In the absence of phospholipid, cryo-TEM revealed bilayer fragments in coexistence with threadlike micelles in mixtures containing the same molar amount of MOPC and OA. External addition of MOPC to preformed EPC liposomes gave rise to a concentration dependent evolution of intermediate structures, including open liposomes and bilayer fragments. The structural rearrangements were found to be slow and permitted visualization of a number of interesting transition structures. In addition to the structural studies, static and time-resolved fluorescence measurements were employed to determine some fundamental parameters for MOPC micelles. The results indicate a critical micelle concentration of close to 5 μM and an aggregation number of approximately 142.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-90315 (URN)10.1021/la010020u (DOI)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2017-12-14Bibliographically approved
2. Adsorption of a PEO-PPO-PEO triblock copolymer on small unilamellar vesicles: equilibrium and kinetic properties and correlation with membrane permeability
Open this publication in new window or tab >>Adsorption of a PEO-PPO-PEO triblock copolymer on small unilamellar vesicles: equilibrium and kinetic properties and correlation with membrane permeability
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2001 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 17, no 13, p. 3902-3911Article in journal (Refereed) Published
Abstract [en]

The adsorption of the triblock copolymer F127, poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide), EO98PO67EO98, onto immobilized small unilamellar vesicles (SUVs) of egg phosphatidylcholine (EPC) has been studied by means of a quartz crystal microbalance (QCM). With this technique we first show that SUVs of EPC adsorb on gold to form a monolayer of vesicles. This supported monolayer of vesicles was then used to follow the adsorption of the F127 polymer onto the lipid membrane surface. The adsorption of F127 was found to be a rapid process, and the measured polymer binding isotherm was fitted to a Freundlich type of isotherm. The maximum, or plateau, adsorbed amount was determined to be of a magnitude similar to that found for adsorption of F127 on hydrophobic surfaces. Furthermore, the desorption of the triblock copolymers from the membrane surface was followed after rinsing the SUV monolayer with pure buffer. It was found that the desorption process displayed essentially the same rapid kinetics as the adsorption process, indicating a weak interaction between the polymers and the lipid membrane. The determined polymer binding isotherm was used to correlate the adsorbed amount of polymer with the polymer-induced leakage of carboxy fluorescein (CF) from the SUVs. It was found that the membrane permeability was increased severalfold already at low surface coverage and that the maximum magnitude of the CF release rate was obtained at, or close to, F127 concentrations giving rise to the maximum adsorbed amount of polymer. In addition, the increased membrane permeability induced by the triblock copolymers was compared with the effect of adding a conventional ethylene oxide (EO) surfactant, Triton X-100, to the SUVs. The result emphasizes the dramatic effect of F127 on the bilayer permeability.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-90316 (URN)10.1021/la0101245 (DOI)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2017-12-14Bibliographically approved
3. Effects caused by PEO-PPO-PEO triblock copolymers on structure and stability of liposomal DOPE dispersions.
Open this publication in new window or tab >>Effects caused by PEO-PPO-PEO triblock copolymers on structure and stability of liposomal DOPE dispersions.
(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90317 (URN)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2011-03-21
4. Linkage identity is a major factor determining the effect of PEGylated surfactants, on permeability in phosphatidylcholine liposomes.
Open this publication in new window or tab >>Linkage identity is a major factor determining the effect of PEGylated surfactants, on permeability in phosphatidylcholine liposomes.
In: Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90318 (URN)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2011-03-21
5. Interaction between pH-sensitive liposomes and model membranes
Open this publication in new window or tab >>Interaction between pH-sensitive liposomes and model membranes
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2003 (English)In: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 104, no 1, p. 361-379Article in journal (Refereed) Published
Abstract [en]

The structure and dynamics of two different pH-sensitive liposome systems were investigated by means of cryo-transmission electron microscopy and different photophysical techniques. Both systems consisted of dioleoylphosphatidylethanolamine (DOPE) and contained either oleic acid (OA) or a novel acid-labile polyethylene glycol-conjugated lipid (DHCho-MPEG5000) as stabiliser. Proton induced leakage, lipid mixing and structural changes were studied in the absence and presence of EPC liposomes, as well as in the presence of liposomes designed to model the endosome membrane. Neither DHCho-MPEG5000- nor OA-stabilised liposomes showed any tendency for fusion with pure EPC liposomes or endosome-like liposomes composed of EPC/DOPE/SM/Cho (40/20/6/34 mol.%). Our investigations showed, however, that incorporation of lipids from the pH-sensitive liposomes into the endosome membrane may lead to increased permeability and formation of non-lamellar structures. Taken together the results suggest that the observed ability of DOPE-containing liposomes to mediate cytoplasmic delivery of hydrophilic molecules cannot be explained by a mechanism based on a direct, and non-leaky, fusion between the liposome and endosome membranes. A mechanism involving destabilisation of the endosome membrane due to incorporation of DOPE, seems more plausible.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-90319 (URN)10.1016/S0301-4622(03)00011-5 (DOI)12834854 (PubMedID)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2017-12-14Bibliographically approved
6. Optimization of drug loading procedures and characterization of liposomal formulations of two novel agents intended for Boron Neutron Capture Therapy (BNCT)
Open this publication in new window or tab >>Optimization of drug loading procedures and characterization of liposomal formulations of two novel agents intended for Boron Neutron Capture Therapy (BNCT)
1999 (English)In: Journal of liposome research, ISSN 0898-2104, E-ISSN 1532-2394, Vol. 9, no 1, p. 53-79Article in journal (Refereed) Published
Abstract [en]

The characterization of two liposomal formulations of boronated DNA-interacting agents has been performed. It is shown that the two boronated drugs, WSA-Water Soluble Acridine and WSP-Water Soluble Phenantridine, can be encapsulated within unilamellar sterically stabilized liposomes with high drug-to-lipid ratios (up to 0.50:1 (mol:mol)), using transmembrane pH gradients. The steric stabilization of the liposomes was accomplished by the addition of DSPE-PEG(2000) (PEG-lipid) to DSPC/Cho lipid mixtures and the composition used was DSPC:Cho:DSPE-PEG 55:40:5 (mol%). The loading of the drugs resulted in drug precipitation in the liposomal aqueous core as observed by cryo-transmission electron microscopy (c-TEM). Moreover, it is shown that when pH gradients across the bilayer were used for remote loading of WSP or when ammonium sulfate gradients were used for remote loading of WSA, the formation of small bilayer fragments (discs) was induced. We present compelling evidence that the formation of discs is a consequence of precipitate growth in the liposomal interior. The precipitate growth causes some of the liposomes to rupture resulting in the above mentioned disc-formation and a substantial decrease in trapping efficiency. The in vitro stability of the drug loaded liposomes was excellent, both in buffer and in 25% human serum. For most of the formulations, the release of the drugs was below or around 10% after 24 hours at 37 degrees C. Furthermore, the influence of initial internal pH and internal buffering capacity on release properties of WSA and WSP were investigated. It is shown that the release profiles of the drugs can be controlled, to a large extent, by varying the composition of the internal liposomal aqueous phase.

Keywords
BNCT, liposome, bilayer discs, drug loading, drug retention
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-90320 (URN)10.3109/08982109909044492 (DOI)000079495400006 ()
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2017-12-14Bibliographically approved
7. Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents
Open this publication in new window or tab >>Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents
Show others...
2002 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 13, no 4, p. 737-743Article in journal (Refereed) Published
Abstract [en]

Liposomes are of interest as drug delivery tools for therapy of cancer and infectious diseases. We investigated conjugation of epidermal growth factor, EGF, to liposomes using the micelle-transfer method. EGF was conjugated to the distal end of PEG−DSPE lipid molecules in a micellar solution and the EGF−PEG−DSPE lipids were then transferred to preformed liposomes, either empty or containing the DNA-binding compound, water soluble acridine, WSA. We found that the optimal transfer conditions were a 1-h incubation at 60 °C. The final conjugate, 125I-EGF−liposome−WSA, contained approximately 5 mol % PEG, 10−15 EGF molecules at the liposome surface, and 104 to 105 encapsulated WSA molecules could be loaded. The conjugate was shown to have EGF-receptor-specific cellular binding in cultured human glioma cells.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-90321 (URN)10.1021/bc0100713 (DOI)
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2017-12-14Bibliographically approved

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