Castile, Jonathan David; (1998) The interaction of multilamellar and freeze-thawed liposomes with poloxamer surfactants. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes the development of a protocol for the production of small liposomes using freeze-thaw extrusion technology and investigations into the interaction of liposomes with poloxamers. Laser diffraction particle size analysis showed that the median diameter of freeze-thawed egg phosphatidylcholine multilamellar vesicles (EPC MLVs) was dependent on their initial diameter and cholesterol content. Dispersion in sodium chloride solutions promoted size increases following freeze-thawing, suggesting that vesicles had aggregated or fused. Addition of poloxamers inhibited size changes, suggesting that poloxamers sterically stabilized these formulations. Ten extrusion passes through two 100 nm pore filters efficiently reduced the diameter of EPC MLVs, measured using photon correlation spectroscopy (PCS), producing relatively monodisperse populations of small liposomes. Freeze-fracture electron microscopy indicated that vesicles were generally unilamellar. Size reduction of liposomes was not significantly affected by lipid concentration or cholesterol content. Differences in the micellization behaviour of poloxamers P338 and P407 obtained from different manufacturers were established using high sensitivity differential scanning calorimetry (HSDSC). Gel permeation chromatography revealed differences in the molecular weight profiles of these samples. PCS, DSC and a quantitative colourimetric assay indicated that the interaction between poloxamers and liposomes was dependent on incubation temperature in addition to poloxamer concentration. Maximum increases in the diameter of small EPC liposomes occurred at temperatures close to poloxamer critical micelle temperatures. DSC investigations indicated that poloxamers interacted with the phospholipid bilayers of dimyristoylphosphatidylcholine MLVs in the Lα and Pβ. states, but not with those in the Lβ state. This suggests that the rigid, close-packed bilayer structure inhibited the interaction, possibly by hindering penetration of poloxamer into the hydrophobic region of the bilayer. Inclusion of poloxamer at the hydration stage of liposome production or exposure to five freeze-thaw cycles improved the interaction between poloxamers and bilayers and therefore could potentially be used to 'load' poloxamers into the bilayers of solid-state liposomes and to maximize the liposome-poloxamer interaction.

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