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Optimization of drug loading procedures and characterization of liposomal formulations of two novel agents intended for Boron Neutron Capture Therapy (BNCT)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical Chemistry.
1999 (English)In: Journal of liposome research, ISSN 0898-2104, E-ISSN 1532-2394, Vol. 9, no 1, 53-79 p.Article 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.

Place, publisher, year, edition, pages
1999. Vol. 9, no 1, 53-79 p.
Keyword [en]
BNCT, liposome, bilayer discs, drug loading, drug retention
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90320DOI: 10.3109/08982109909044492ISI: 000079495400006OAI: oai:DiVA.org:uu-90320DiVA: diva2:162630
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2013-05-30Bibliographically approved
In thesis
1. Liposomes for Drug Delivery: from Physico-chemical Studies to Applications
Open this publication in new window or tab >>Liposomes for Drug Delivery: from Physico-chemical Studies to Applications
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. 71 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 826
Keyword
Physical chemistry, liposome, steric stabilisation, BNCT, cryo-TEM, EGF, targeting, stability, permeability, pH-sensitive liposomes, triggered release, Fysikalisk kemi
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-3390 (URN)91-554-5592-1 (ISBN)
Public defence
2003-05-23, B41, BMC, Uppsala, 10:15
Opponent
Supervisors
Available from: 2003-04-30 Created: 2003-04-30Bibliographically approved

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Edwards, Katarina

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